KR20200045517A - 병태 및 질환 치료용 안티센스 올리고머 - Google Patents

병태 및 질환 치료용 안티센스 올리고머 Download PDF

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KR20200045517A
KR20200045517A KR1020207008236A KR20207008236A KR20200045517A KR 20200045517 A KR20200045517 A KR 20200045517A KR 1020207008236 A KR1020207008236 A KR 1020207008236A KR 20207008236 A KR20207008236 A KR 20207008236A KR 20200045517 A KR20200045517 A KR 20200045517A
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nucleotides
scn1a
aso
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이사벨 아즈나레즈
조우 한
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스톡 테라퓨틱스, 인크.
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Abstract

유전자 SCN1A에서 선택적 스플라이싱 이벤트는 비생산적 mRNA 전사체를 초래할 수 있고, 이는 결국 비정상적 단백질 발현을 초래할 수 있고, SCN1A 유전자에서 선택적 스플라이싱 이벤트를 표적화할 수 있는 치료제는 드라벳 증후군 환자에서 기능성 단백질의 발현 수준을 조절하고/거나 비정상적 단백질 발현을 억제할 수 있다. 이러한 치료제는 SCN1A, SCN8A 또는 SCN5A 단백질 결핍에 의해 야기된 병태를 치료하는 데 사용될 수 있다.

Description

병태 및 질환 치료용 안티센스 올리고머
상호 참조
본 출원은 2017년 8월 25일에 출원된 미국 가출원 제62/550,462호, 2017년 10월 23일에 출원된 미국 가출원 제62/575,901호, 2018년 5월 4일에 출원된 미국 가출원 제62/667,356호, 2018년 5월 15일에 출원된 미국 가출원 제62/671,745호의 이익을 주장하며, 이들 각각은 그 전문이 본원에 참고로 포함된다.
발명의 배경
신경계 장애는 신경 흥분성, 뉴런 상호 작용, 및 전체적인 뇌 기능을 매개하는 이온 통로(채널)의 기능 장애를 특징으로 하는 이온통로병증과 종종 관련된다. 뉴런 전압 게이팅 나트륨 채널의 알파 세공 형성 서브유닛을 코딩하는 SCN1A-SCN2A-SCN3A 유전자 클러스터의 일부인 SCN1A 유전자의 돌연변이는 드라벳 증후군(DS: Dravet Syndrome)과 같은 질환 및 병태의 질환 수의 발달과 관련이 있다(Miller, et al., 1993-2015, GeneReviews, Eds. Pagon RA, et al. Seattle (WA): University of Washington, Seattle, Bookshelf ID: NBK1318, and Mulley, et al., 2005, Hum. Mutat. 25: 535-542).
발명의 요약
특정 실시양태에서, SCN1A 단백질을 코딩하는, 넌센스 매개 RNA 붕괴 유도 엑손(non-sense mediated RNA decay-inducing exon)을 함유하는 mRNA(NMD 엑손 mRNA)를 갖는 세포에서 SCN1A 단백질의 발현을 조절하는 방법으로서, 치료제를 세포에 접촉시키는 단계를 포함하고, 그로 인하여 치료제가 SCN1A 단백질을 코딩하는 NMD 엑손 mRNA로부터 NMD 엑손의 스플라이싱을 조절하고, 이로써 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 조절하고, SCN1A 단백질의 발현을 조절하는 것인 방법이 본원에서 개시된다. 일부 실시양태에서, 치료제는 (a) SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 결합하거나; (b) NMD 엑손 mRNA의 스플라이싱에 관여하는 인자의 결합을 조절하거나; (c) (a)와 (b)의 조합이다. 일부 실시양태에서, 치료제는 표적화된 부분의 영역으로부터 NMD 엑손의 스플라이싱에 관여하는 인자의 결합을 방해한다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손에 근접해 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 5' 말단의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 상류에 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 5' 말단의 적어도 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 상류에 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 3' 말단의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 하류에 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 3' 말단의 적어도 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 하류에 있다. 일부 실시양태에서, 표적화된 부분은 SCN1A를 코딩하는 NMD 엑손 mRNA의 2개의 표준 엑손 영역 사이의 인트론 영역에 위치하며, 인트론 영역은 NMD 엑손을 함유한다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손과 적어도 부분적으로 중첩된다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 상류 인트론과 적어도 부분적으로 중첩된다. 일부 실시양태에서, 표적화된 부분은 5' NMD 엑손-인트론 접합부 또는 3' NMD 엑손-인트론 접합부를 포함한다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손 내에 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 약 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30개 또는 그 이상의 연속적인 뉴클레오티드를 포함한다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA는 서열 번호 2 또는 7 내지 10 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함한다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA는 서열 번호 1 또는 3 내지 6과 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 유전자 서열에 의해 코딩된다. 일부 실시양태에서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,803의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 상류에 있다. 일부 실시양태에서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,803의 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 상류에 있다. 일부 실시양태에서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,740의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 하류에 있다. 일부 실시양태에서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,740의 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 하류에 있다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 서열 번호 2 또는 7 내지 10의 적어도 8개의 인접한 핵산을 포함하는 영역과 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO: antisense oligomer)이며 ASO는 서열 번호 21 내지 67, 210 내지 256, 또는 304 내지 379 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함한다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x 내에 있다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 42 내지 50, 또는 231 내지 239 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함한다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x의 상류 또는 하류에 있다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21 내지 38, 53 내지 67, 210 내지 227, 또는 242 내지 256 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함한다. 일부 실시양태에서, NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 엑손 20x의 엑손-인트론 접합부를 포함한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 39 내지 41, 51, 52, 228 내지 230, 240, 또는 241 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함한다. 일부 실시양태에서, 치료제는 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 촉진한다. 일부 실시양태에서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제는 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제와 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가한다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 증가시킨다. 일부 실시양태에서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 양은 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가한다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질의 발현을 증가시킨다. 일부 실시양태에서, 치료제와 접촉된 세포에서 생성된 SCN1A의 양은 대조군 세포에서 생성된 SCN1A의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가한다. 일부 실시양태에서, 치료제는 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 억제한다. 일부 실시양태에서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제는 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제와 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소한다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 감소시킨다. 일부 실시양태에서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 양은 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소한다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질의 발현을 감소시킨다. 일부 실시양태에서, 치료제와 접촉된 세포에서 생성된 SCN1A의 양은 대조군 세포에서 생성된 SCN1A의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로티오에이트 결합 또는 포스포로디아미데이트 결합을 포함하는 백본 변형을 포함한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로디아미데이트 모르폴리노, 잠금 핵산, 펩티드 핵산, 2'-O-메틸, 2'-플루오로, 또는 2'-O-메톡시에틸 모이어티를 포함한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 하나 이상의 변형된 당 모이어티를 포함한다. 일부 실시양태에서, 각각의 당 모이어티는 변형된 당 모이어티이다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 8 내지 50개의 핵염기, 8 내지 40개의 핵염기, 8 내지 35개의 핵염기, 8 내지 30개의 핵염기, 8 내지 25개의 핵염기, 8 내지 20개의 핵염기, 8 내지 15개의 핵염기, 9 내지 50개의 핵염기, 9 내지 40개의 핵염기, 9 내지 35개의 핵염기, 9 내지 30개의 핵염기, 9 내지 25개의 핵염기, 9 내지 20개의 핵염기, 9 내지 15개의 핵염기, 10 내지 50개의 핵염기, 10 내지 40개의 핵염기, 10 내지 35개의 핵염기, 10 내지 30개의 핵염기, 10 내지 25개의 핵염기, 10 내지 20개의 핵염기, 10 내지 15개의 핵염기, 11 내지 50개의 핵염기, 11 내지 40개의 핵염기, 11 내지 35개의 핵염기, 11 내지 30개의 핵염기, 11 내지 25개의 핵염기, 11 내지 20개의 핵염기, 11 내지 15개의 핵염기, 12 내지 50개의 핵염기, 12 내지 40개의 핵염기, 12 내지 35개의 핵염기, 12 내지 30개의 핵염기, 12 내지 25개의 핵염기, 12 내지 20개의 핵염기, 또는 12 내지 15개의 핵염기로 이루어진다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 단백질을 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 98%, 적어도 99%, 또는 100% 상보적이다. 일부 실시양태에서, 방법은 SCN1A mRNA 또는 단백질 발현을 평가하는 단계를 추가로 포함한다. 일부 실시양태에서, 세포는 생체 외 세포이다.
특정 실시양태에서, 치료를 필요로 하는 대상체의 세포에서 SCN1A 단백질의 발현을 조절함으로써 대상체에서 질환 또는 병태를 치료하는 방법으로서, 대상체의 세포를 NMD 엑손을 함유하고 SCN1A를 코딩하는 세포에서 mRNA로부터 넌센스 매개 mRNA 붕괴 유도 엑손(NMD 엑손)의 스플라이싱을 조절하는 치료제와 접촉시키는 단계를 포함하고, 그로 인하여 대상체의 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 조절하고, SCN1A 단백질의 발현을 조절하는 것인 방법이 본원에서 개시된다. 일부 실시양태에서, 치료제 (a)는 (a) SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 결합하거나; (b) NMD 엑손 mRNA의 스플라이싱에 관여하는 인자의 결합을 조절하거나; (c) (a)와 (b)의 조합이다. 일부 실시양태에서, 치료제는 표적 부분의 영역으로부터 NMD 엑손의 스플라이싱에 관여하는 인자의 결합을 방해한다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손에 근접해 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 5' 말단의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 상류에 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 5' 말단의 적어도 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 상류에 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 3' 말단의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 하류에 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 3' 말단의 적어도 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 하류에 있다. 일부 실시양태에서, 표적화된 부분은 SCN1A를 코딩하는 NMD 엑손 mRNA의 2개의 표준 엑손 영역 사이의 인트론 영역에 위치하며, 인트론 영역은 NMD 엑손을 함유한다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손과 적어도 부분적으로 중첩된다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 상류 인트론과 적어도 부분적으로 중첩된다. 일부 실시양태에서, 표적화된 부분은 5' NMD 엑손-인트론 접합부 또는 3' NMD 엑손-인트론 접합부를 포함한다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손 내에 있다. 일부 실시양태에서, 표적화된 부분은 NMD 엑손의 약 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30개 또는 그 이상의 연속적인 뉴클레오티드를 포함한다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA는 서열 번호 2 또는 7 내지 10 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함한다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA는 서열 번호 1 또는 3 내지 6과 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 유전자 서열에 의해 코딩된다. 일부 실시양태에서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,803의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 상류에 있다. 일부 실시양태에서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,803의 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 상류에 있다. 일부 실시양태에서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,740의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 하류에 있다. 일부 실시양태에서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,740의 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 하류에 있다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 서열 번호 2 또는 7 내지 10의 적어도 8개의 인접한 핵산을 포함하는 영역과 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 서열 번호 21 내지 67, 210 내지 256, 또는 304 내지 379 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함한다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x 내에 있다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 42 내지 50, 또는 231 내지 239 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함한다. 일부 실시양태에서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x의 상류 또는 하류에 있다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21 내지 38, 53 내지 67, 210 내지 227, 또는 242 내지 256 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함한다. 일부 실시양태에서, NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 엑손 20x의 엑손-인트론 접합부를 포함한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 39 내지 41, 51, 52, 228 내지 230, 240, 또는 241 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함한다. 일부 실시양태에서, 치료제는 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 촉진한다. 일부 실시양태에서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제는 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제와 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가한다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 증가시킨다. 일부 실시양태에서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 양은 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가한다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질의 발현을 증가시킨다. 일부 실시양태에서, 치료제와 접촉된 세포에서 생성된 SCN1A의 양은 대조군 세포에서 생성된 SCN1A의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가한다. 일부 실시양태에서, 치료제는 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 억제한다. 일부 실시양태에서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제는 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제와 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소한다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 감소시킨다. 일부 실시양태에서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 양은 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소한다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질의 발현을 감소시킨다. 일부 실시양태에서, 치료제와 접촉된 세포에서 생성된 SCN1A의 양은 대조군 세포에서 생성된 SCN1A의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로티오에이트 결합 또는 포스포로디아미데이트 결합을 포함하는 백본 변형을 포함한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로디아미데이트 모르폴리노, 잠금 핵산, 펩티드 핵산, 2'-O-메틸, 2'-플루오로, 또는 2'-O-메톡시에틸 모이어티를 포함한다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 하나 이상의 변형된 당 모이어티를 포함한다. 일부 실시양태에서, 각각의 당 모이어티는 변형된 당 모이어티이다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 8 내지 50개의 핵염기, 8 내지 40개의 핵염기, 8 내지 35개의 핵염기, 8 내지 30개의 핵염기, 8 내지 25개의 핵염기, 8 내지 20개의 핵염기, 8 내지 15개의 핵염기, 9 내지 50개의 핵염기, 9 내지 40개의 핵염기, 9 내지 35개의 핵염기, 9 내지 30개의 핵염기, 9 내지 25개의 핵염기, 9 내지 20개의 핵염기, 9 내지 15개의 핵염기, 10 내지 50개의 핵염기, 10 내지 40개의 핵염기, 10 내지 35개의 핵염기, 10 내지 30개의 핵염기, 10 내지 25개의 핵염기, 10 내지 20개의 핵염기, 10 내지 15개의 핵염기, 11 내지 50개의 핵염기, 11 내지 40개의 핵염기, 11 내지 35개의 핵염기, 11 내지 30개의 핵염기, 11 내지 25개의 핵염기, 11 내지 20개의 핵염기, 11 내지 15개의 핵염기, 12 내지 50개의 핵염기, 12 내지 40개의 핵염기, 12 내지 35개의 핵염기, 12 내지 30개의 핵염기, 12 내지 25개의 핵염기, 12 내지 20개의 핵염기, 또는 12 내지 15개의 핵염기로 이루어진다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 단백질을 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 98%, 적어도 99%, 또는 100% 상보적이다. 일부 실시양태에서, 방법은 SCN1A mRNA 또는 단백질 발현을 평가하는 단계를 추가로 포함한다. 일부 실시양태에서, 질환 또는 병태는 Nav1.1의 기능 상실 돌연변이에 의해 유발된다. 일부 실시양태에서, 질환 또는 병태는 SCN1A 유전자의 반가불충분성과 관련되며, 대상체는 기능성 SCN1A를 코딩하는 제1 대립 유전자, 및 SCN1A가 생성되지 않거나 감소한 수준으로 생성되는 제2 대립 유전자, 또는 비기능성 SCN1A 또는 부분 기능성 SCN1A를 코딩하는 제2 대립 유전자를 갖는다. 일부 실시양태에서, 질환 또는 병태는 뇌병증이다. 일부 실시양태에서, 뇌병증은 간질성 뇌병증이다. 일부 실시양태에서, 질환 또는 병태는 드라벳 증후군(DS); 유아기의 중증 근간대성 뇌전증(SMEI: severe myoclonic epilepsy of infancy) 경계성(borderland)(SMEB); 열성 발작(FS: Febrile seizure); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+: epilepsy, generalized, with febrile seizures plus); 조기 유아 간질성 뇌병증 13(epileptic encephalopathy, early infantile, 13); 잠재성(cryptogenic) 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP: sudden unexpected death in epilepsy); 동기능 부전 증후군 1(sick sinus syndrome 1); 자폐증; 또는 유아기의 악성 이동 부분 발작이다. 일부 실시양태에서, GEFS+는 열성 발작 플러스를 동반하는 전신 뇌전증 2형(epilepsy, generalized, with febrile seizures plus, type 2)이다. 일부 실시양태에서, 열성 발작은 가족성 열성 발작 3A(Febrile seizures, familial, 3A)이다. 일부 실시양태에서, SMEB는 전신 극파가 없는 SMEB(SMEB-SW: SMEB without generalized spike wave), 근간대성 발작이 없는 SMEB(SMEB-M: SMEB without myoclonic seizures), SMEI의 하나 초과의 특징이 결여된 SMEB(SMEB-O: SMEB lacking more than one feature of SMEI), 또는 전신 강직성 간대 발작을 동반한 난치성 소아기 뇌전증(ICEGTC: intractable childhood epilepsy with generalized tonic-clonic seizures)이다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 촉진하고 SCN1A의 발현을 증가시킨다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 22 내지 24, 26, 27, 29 내지 35, 37 내지 62, 64 내지 67, 또는 304 내지 379 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함한다. 일부 실시양태에서, 질환 또는 병태는 Nav1.1의 기능 획득 돌연변이에 의해 유발된다. 일부 실시양태에서, 대상체는 세포에서 SCN1A가 증가한 수준으로 생성되는 대립 유전자, 또는 Nav1.1의 증가한 활성을 유도하는 돌연변이 SCN1A를 코딩하는 대립 유전자를 갖는다. 일부 실시양태에서, 질환 또는 병태는 편두통이다. 일부 실시양태에서, 편두통은 가족성 편마비 편두통 3(migraine, familial hemiplegic, 3)이다. 일부 실시양태에서, 질환 또는 병태는 Nav1.1 유전성 뇌전증이다. 일부 실시양태에서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 억제하고 SCN1A의 발현을 감소시킨다. 일부 실시양태에서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21, 25, 28, 36 또는 63 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함한다. 일부 실시양태에서, 대상체는 인간이다. 일부 실시양태에서, 대상은 비인간 동물이다. 일부 실시양태에서, 대상체는 태아, 배아, 또는 소아이다. 일부 실시양태에서, 치료제는 대상체의 수막공간내(intrathecal) 주사, 뇌실내(intracerebroventricular) 주사, 복강내 주사, 근육내 주사, 피하 주사, 안내(intravitreal) 주사, 또는 정맥내 주사에 의해 투여된다. 일부 실시양태에서, 방법은 대상체에게 제2 치료제를 투여하는 단계를 추가로 포함한다. 일부 실시양태에서, 제2 치료제는 소분자이다. 일부 실시양태에서, 제2 치료제는 ASO이다. 일부 실시양태에서, ASO는 서열 번호 115 내지 161 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함한다. 일부 실시양태에서, 제2 치료제는 인트론 유지(intron retention)를 교정한다. 일부 실시양태에서, 질환 또는 병태는 알츠하이머병, SCN2A 뇌병증, SCN8A 뇌병증, 또는 SCN5A 부정맥이다. 일부 실시양태에서, 질환 또는 병태는 알츠하이머병, SCN2A 뇌병증, SCN8A 뇌병증, 또는 SCN5A 부정맥이다. 일부 실시양태에서, 세포는 생체 외 세포이다.
참고의 포함
본 명세서에서 언급된 모든 간행물, 특허, 및 특허 출원은 각각의 개별 간행물, 특허, 또는 특허 출원이 참고로 포함된 것으로 구체적이고 개별적으로 명시된 것과 동일한 정도로 본원에 참고로 포함된다.
본 발명의 신규 특징은 첨부된 청구 범위에 구체적으로 기재되어 있다. 본 발명의 특징 및 장점은 본 발명의 원리가 이용되는 예시적인 실시양태 및 하기의 첨부 도면을 설명하는 다음의 상세한 설명을 참조하여 더 잘 이해될 것이다:
[도 1]은 넌센스 매개 mRNA 붕괴 유도 엑손을 함유하는 표적 mRNA(NMD 엑손 mRNA), 및 전장의 표적 단백질 또는 기능성 RNA의 발현을 증가시키는 넌센스 매개 mRNA 붕괴 유도 엑손의 치료제 매개 배제의 개략도를 도시한다. [도 1a]는 핵 및 세포질 구획으로 분할된 세포를 나타낸다. 핵에서, 표적 유전자의 프리-mRNA(pre-mRNA) 전사체는 스플라이싱을 거쳐 mRNA를 생성하고, 이 mRNA는 세포질로 유출되고 표적 단백질로 번역된다. 이 표적 유전자에 대해, mRNA의 일부 분획은 세포질에서 분해되는 넌센스 매개 mRNA 붕괴 유도 엑손을 함유하여(NMD 엑손 mRNA) 표적 단백질 생산으로 이어지지 않는다. [도 1b]는 핵 및 세포질 구획으로 분할된 동일한 세포의 예를 보여준다. 안티센스 올리고머(ASO)와 같은 치료제에 의한 치료는 넌센스 매개 mRNA 붕괴 유도 엑손의 배제를 촉진하고 mRNA의 증가를 초래하며, 이는 결국 더 높은 수준의 표적 단백질로 번역된다. [도 1c]는 넌센스 매개 mRNA 붕괴 유도 엑손의 치료적 ASO 매개 배제를 개략적으로 나타내며, 이는 비생산적 mRNA를 생산적 mRNA로 바꾸고 생산적 mRNA로부터 전장의 표적 단백질의 발현을 증가시킨다.
[도 2]는 SCN1A 유전자에서 예시적인 넌센스 매개 mRNA 붕괴(NMD) 유도 엑손의 확인을 도시한다. 비교 게놈학을 사용하여 SCN1A 유전자에서 NMD 유도 엑손의 확인을 UCSC 게놈 브라우저에서 시각화하여 나타낸다. 상단 패널은 스케일링할 SCN1A 유전자를 도식적으로 표현하여 나타낸다. 100종의 척추동물 종에 대한 보존 수준을 피크로 나타낸다. 가장 높은 피크는 엑손(검은 박스)에 해당하는 한편, 대부분의 인트론(화살표가 있는 선)에는 피크가 관찰되지 않는다. 중간 패널에 나타낸 인트론 20(NM_006920)에서 보존 피크가 확인된다. 보존된 서열을 검사하여 3' 및 5' 스플라이스 부위(밑줄 친 서열)의 측면에 위치한 64 bp의 엑손 유사 서열(하부 패널, 회색으로 강조된 서열)을 확인하였다. 이 엑손의 포함은 프레임 시프트 및 엑손 21에 조기 종결 코돈의 도입을 초래하여 전사체를 표적으로 만든다.
[도 3a]는 시클로헥시미드 처리를 통한 NMD 유도 엑손의 확증을 도시한다. DMSO 처리(CHX-) 또는 시클로헥시미드 처리(CHX+) Neuro 2A(마우스 신경 전구 세포)의 세포질 RNA 및 엑손 21 및 하류 엑손 내 프라이머를 사용한 RT-PCR 분석으로 NMD 유도 엑손(21x)에 상응하는 밴드의 존재를 확증하였다. 생성물의 동일성은 서열분석에 의해 확증하였다. 밴드의 밀도 측정 분석을 수행하여 총 SCN1A 전사체의 퍼센트 엑손 21x 포함을 계산하였다. NMD를 억제하는 시클로헥시미드로 Neuro 2A의 처리(CHX+)는 세포질 분획에서 NMD 유도 엑손 21x에 상응하는 생성물의 2배 증가를 초래하였다(연회색 막대, CHX-와 진회색 막대, CHX+ 비교).
[도 3b]는 시클로헥시미드 처리를 통한 NMD 유도 엑손의 확증을 도시한다. DMSO 처리(CHX-) 또는 시클로헥시미드 처리(CHX+) RenCell VM(인간 신경 전구 세포)의 세포질 RNA 및 엑손 20 및 엑손 23 내 프라이머를 사용한 RT-PCR 분석으로 NMD 유도 엑손(20x)에 상응하는 밴드의 존재를 확증하였다. 생성물의 동일성은 서열분석에 의해 확증하였다. 밴드의 밀도 측정 분석을 수행하여 총 SCN1A 전사체의 퍼센트 엑손 20x 포함을 계산하였다. NMD를 억제하는 시클로헥시미드로 RenCell VM의 처리(CHX+)는 세포질 분획에서 NMD 유도 엑손 20x에 상응하는 생성물의 2배 증가를 초래하였다(참조: 연회색 막대, CHX-, 진회색 막대, CHX+).
[도 4]는 예시적인 SCN1A 엑손 20x 영역 ASO 워크(walk)를 도시한다. 2'-MOE ASO, PS 백본을 사용하여 3' 스플라이스 부위의 상류 서열, 3' 스플라이스 부위에 걸친 서열, 엑손 20x 서열, 5' 스플라이스 부위에 걸친 서열, 및 5' 스플라이스 부위의 하류 서열을 표적화하는 SCN1A 엑손 20x 영역에 수행된 ASO 워크를 도식으로 표현하여 나타낸다. ASO는 한 번에 5 뉴클레오티드를 이동시켜 이들 영역을 덮도록 설계하였다.
[도 5a]는 RT-PCR에 의해 평가된 SCN1A 엑손 20x 영역 ASO 워크를 도시한다. 대표적인 PAGE는 짐노틱(gymnotic) 흡수에 의해 RenCell VM 세포에서 모의 처리된(Sham), SMN-대조군 ASO 처리된(SMN), 또는 실시예 및 [도 4]의 설명에서 본원에 기재된 바와 같이 엑손 20x 영역을 표적화하는 20 μM 농도의 2'-MOE ASO로 처리된 SCN1A의 SYBR-세이프(SYBR-safe) 염색된 RT-PCR 생성물을 보여준다. 엑손 20x 포함(상부 밴드) 및 전장(엑손 20x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였다.
[도 5b]는 [도 5a]의 데이터로부터 퍼센트 엑손 20x 포함을 플로팅한 그래프를 도시한다. 검은 선은 Sham에 대해 변화없음을 나타낸다.
[도 5c]는 RPL32 내부 대조군에 정규화된 전장 생성물의 그래프를 도시하고 Sham에 대한 배수 변화를 플로팅한다. 검은 선은 Sham에 대하여 1의 비율 및 변화없음을 나타낸다.
[도 6]은 RT-qPCR에 의해 평가된 예시적인 SCN1A 엑손 20x 영역 ASO 워크를 도시한다. [도 5]에 나타낸 바와 같이 SYBR-세이프 RT-PCR에 의해 평가된 동일한 ASO 흡수 실험을 사용하여 얻은, RPL32에 정규화된 SYBR-그린 RT-qPCR SCN1A 증폭 결과는 Sham에 대한 배수 변화로서 플로팅하며, 이는 SYBR-세이프 RT-PCR 결과를 확증해준다. 검은 선은 1의 비율(Sham과 대하여 변화없음)을 나타낸다.
[도 7a]는 나트륨 전압 게이팅 채널 알파 서브유닛 구성원의 표를 도시한다. 화살표는 [도 7b]의 막대 색에 해당한다. X는 발현이 검출되지 않음을 나타낸다.
[도 7b]는 표적 선택도를 평가하기 위해 SCN1A, SCN2A, SCN3A, SCN8A, 및 SCN9A의 태크맨(Taqman) qPCR에 의해 평가된 선택된 ASO를 도시한다. Ex20x+1, IVS20x+18, 및 IVS20x+33 ASO를 사용하여 얻은, RPL32에 정규화된 태크맨-qPCR 증폭 결과는 Sham에 대한 배수 변화로서 플로팅한다. 검은 선은 1의 비율(Sham과 대하여 변화없음)을 나타낸다.
[도 8a]는 CXH 처리된 세포에서 선택된 ASO의 예시적인 용량 의존적 효과를 도시한다. RNAiMAX 형질 감염에 의해 Neuro 2A(마우스 신경 모세포종) 세포에서 모의 처리된(Sham, RNAiMAX 단독), 또는 엑손 21x(마우스 명명법, 인간 엑손 20x에 해당)를 표적화하는 30nM, 80nM, 및 200nM 농도의 Ex21x+1 2'-MOE ASO로 처리된 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물을 나타내는 대표적인 PAGE를 나타낸다. Ex21x+1(마우스 명명법)과 Ex20x+1(인간 명명법)은 동일하다. 엑손 20x 포함(상부 밴드) 및 전장(엑손 20x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였다.
[도 8b]는 [도 7a]의 데이터로부터 퍼센트 엑손 20x 포함을 플로팅한 그래프를 도시한다. 검은 선은 Sham에 대하여 변화없음을 나타낸다.
[도 8c]는 Hprt 내부 대조군에 정규화된 전장 생성물의 예시적인 그래프를 도시하고, Sham에 대한 배수 변화를 플로팅한다. 검은 선은 Sham에 대하여 1의 비율 및 변화없음을 나타낸다.
[도 9a]는 C57BL6J 마우스(수컷, 3개월령)에서 선택된 ASO의 안내(IVT) 주사의 예시적인 결과를 도시한다. PBS 주사된(1μL) 좌안(-) 또는 IVS20x-21, Ex21x+1, IVS21x+18, IVS21x+33 또는 Cep290(음성 대조군 ASO; Gerard et al, Mol . Ther. Nuc . Ac., 2015), 10mM 농도의 2'-MOE ASO 주사된(1μL) 우안(+)으로부터 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물의 PAGE 겔을 나타낸다. Ex21x+1, IVS21x+18, 및 IVS21x+33(마우스 명명법)과 Ex20x+1, IVS20x+18, 및 IVS20x+33(인간 명명법)은 동일하다. 엑손 21x 포함(상부 밴드) 및 전장(엑손 21x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였다.
[도 9b]는 [도 9a]의 데이터로부터 퍼센트 엑손 21x 포함을 플로팅한 그래프를 도시한다. 흰색 막대는 ASO 주사된 눈에 해당하고 회색 막대는 PBS 주사된 눈에 해당한다(각 그룹에서 n = 5).
[도 9c]는 Gapdh 내부 대조군에 정규화된 전장 생성물의 그래프를 도시하며 PBS 주사된 눈에 대한 ASO 주사된 눈의 배수 변화를 플로팅한다. 검은 선은 PBS에 대하여 1의 비율 및 변화없음을 나타낸다(각 그룹에서 n = 5).
[도 10a]는 C57BL6J 마우스(수컷, 3개월령)에서 선택된 ASO의 뇌실내(ICV) 주사의 예시적인 결과를 도시한다. 주사되지 않은(-, ASO 없는 대조군) 또는 300 μg의 Cep290(음성 대조군 ASO; Gerard et al, Mol . Ther . Nuc . Ac., 2015), Ex21x+1, IVS21x+18, IVS21x+33 2'-MOE ASO 주사된 뇌로부터 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물의 PAGE 겔을 나타낸다. Ex21x+1, IVS21x+18, 및 IVS21x+33(마우스 명명법)과 Ex20x+1, IVS20x+18, 및 IVS20x+33(인간 명명법)은 동일하다. 엑손 21x 포함(상부 밴드) 및 전장(엑손 21x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였다.
[도 10b] 는 [도 10a]의 데이터로부터 퍼센트 엑손 21x 포함을 플로팅한 그래프를 도시한다(n = 6(각각의 표적화 ASO), n = 5(Cep290 ASO), n = 1(주사되지 않음, ASO 없는 대조군)).
[도 10c]는 엑손 21 및 22 접합부에 걸친 2개의 상이한 프로브를 사용하여 수행된 태크맨 qPCR 분석 결과의 그래프를 도시한다. 생성물을 Gapdh 내부 대조군에 정규화하였고 Cep290 주사된 뇌에 대한 ASO 주사된 뇌의 배수 변화를 플로팅한다. 검은 선은 Cep290에 대하여 1의 비율 및 변화없음을 나타낸다(n = 6(각각의 표적화 ASO), n = 5(Cep290 ASO), n = 1(주사되지 않음, ASO 없는 대조군)).
[도 11a]는 C57BL6J 마우스(수컷, 3 개월령)에서 선택된 ASO의 뇌실내(ICV) 주사의 예시적인 결과를 도시한다. 300ug의 Cep290(음성 대조군 ASO; Gerard et al, Mol . Ther . Nuc . Ac., 2015), 또는 33ug, 100ug, 및 300ug의 Ex21x+1 2'-MOE ASO 주사된 뇌로부터 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물의 PAGE 겔을 나타낸다. Ex21x+1(마우스 명명법)과 Ex20x+1(인간 명명법)은 동일하다. 엑손 21x 포함(상부 밴드) 및 전장(엑손 21x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였다.
[도 11b]는 [도 11a]의 데이터(각 그룹 n = 5)로부터 퍼센트 엑손 21x 포함을 플로팅한 그래프를 도시한다.
[도 11c]는 엑손 21 및 22 접합부에 걸친 2개의 상이한 프로브를 사용하여 수행된 태크맨 qPCR 분석 결과의 그래프를 도시한다. 생성물을 Gapdh 내부 대조군에 정규화하였고 Cep290 주사된 뇌에 대한 ASO 주사된 뇌의 배수 변화를 플로팅한다. 검은 선은 Cep290에 대하여 1의 비율 및 변화없음을 나타낸다(각 그룹 n = 5).
[도 12a]는 C57BL6J 마우스(생후 2일)에서 선택된 ASO의 뇌실내(ICV) 주사의 예시적인 결과를 도시한다. 주사되지 않은(-, ASO 없는 대조군), 또는 20ug의 Ex21x+1 2'-MOE ASO 주사된 뇌로부터 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물의 PAGE 겔을 나타낸다. 엑손 21x 포함(상부 밴드) 및 전장(엑손 21x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였다. Ex21x+1(마우스 명명법)과 Ex20x+1(인간 명명법)은 동일하다.
[도 12b]는 [도 12a]의 데이터(각 그룹 n = 4)로부터 퍼센트 엑손 21x 포함을 플로팅한 그래프를 도시한다.
[도 12c]는 엑손 21 및 22 접합부에 걸친 2개의 상이한 프로브를 사용하여 수행된 태크맨 qPCR 분석 결과의 그래프를 도시한다. 생성물을 Gapdh 내부 대조군에 정규화하였고 ASO 없는 대조군 뇌에 대한 ASO 주사된 뇌의 배수 변화를 플로팅한다. 검은 선은 ASO 없는 대조군에 대하여 1의 비율 및 변화없음을 나타낸다(각 그룹 n = 4).
[도 13a]는 지시된 마우스 CNS 샘플에 퍼센트 엑손 21x 포함을 플로팅한 그래프를 도시한다.
[도 13b]는 지시된 인간 CNS 샘플에서 퍼센트 엑손 20x 포함을 플로팅한 그래프를 도시한다.
[도 14a]는 지시된 용량에서 엑손 21x 포함의 퍼센트 감소를 플로팅한 그래프를 도시한다.
[도 14b]는 지시된 용량에서 Scn1a mRNA의 퍼센트 증가를 플로팅한 그래프를 도시한다.
[도 14c]는 지시된 용량에서 Nav 1.1 단백질 수준의 퍼센트 증가를 플로팅한 그래프를 도시한다.
[도 15a]는 지시된 용량에서 엑손 21x 포함의 퍼센트 감소를 플로팅한 그래프를 도시한다.
[도 15b]는 지시된 용량에서 Scn1a mRNA의 퍼센트 증가를 플로팅한 그래프를 도시한다.
[도 16]은 표적 선택도를 평가하기 위해 생후 2일 마우스에서 ICV 주사를 통해 10ug 용량으로 투여된 선택된 Scn1a 표적화 ASO를 주사 후 5일에 SCN1A , SCN2A , SCN3A, SCN4A , SCN5A , SCN7A , SCN8A , SCN9A , SCN10A , 및 SCN11A의 태크맨 qPCR에 의해 평가하여 도시한다. Ex20x+1 ASO를 사용하여 얻은, Gapdh에 정규화된 태크맨-qPCR 증폭 결과는 PBS 주사된 마우스에 대한 배수 변화로서 플로팅한다.
[도 17]은 야생형(WT) 또는 129S-Scn1atm1Kea x C57BL/6J 교배의 이종 접합 드라벳 마우스(HET) F1 마우스에서 지시된 용량의 선택된 ASO의 출생 2일 후 뇌실내(ICV) 주사로부터 주사 3일 후의 예시적인 결과를 나타낸다.
[도 17a]는 엑손 21 및 22에 걸친 프로브를 사용하여 수행된 태크맨 qPCR 분석 결과의 그래프를 도시한다. 생성물을 Gapdh 내부 대조군에 정규화하였고 PBS 주사된 뇌에 대한 ASO 주사된 뇌의 배수 변화를 플로팅한다.
[도 17b]는 항-Nav1.1 항체를 사용하여 수행된 웨스턴 블롯의 결과의 그래프를 도시한다. 생성물을 폰소(Ponceau) 염색된 밴드에 정규화하였고 PBS 주사된 뇌에 대한 ASO 주사된 뇌의 배수 변화를 플로팅한다.
[도 18]은 자유 흡수를 통한 RenCell에서의 SCN1A 엑손 20x 영역 ASO 마이크로 워크의 예시적인 결과를 도시한다. ASO는 한 번에 1 뉴클레오티드를 이동 하거나(6 내지 41) ASO 17의 길이를 줄임으로써(1 내지 5) [도 6]에서 이전에 확인된 3개의 표적화 ASO(별표로 표시됨) 주위의 영역을 덮도록 설계하였다. 그래프는 SYBR-그린 qPCR에 의해 측정된 퍼센트 엑손 20x 포함을 도시한다. 검은 선은 ASO가 없는 것(-)에 대하여 변화없음을 나타낸다.
[도 19]는 SCN1A 표적화 ASO의 주사 후 시간 경과에 따른 마우스의 관상 뇌 슬라이스에서 Scn1a mRNA의 수준증가를 플로팅한 그래프이다. 도시된 바와 같이, Scn1a mRNA의 수준증가는 주사 후 적어도 80일 동안 유지되었다.
[도 20]은 드라벳 마우스 모델에서 SCN1A 표적화 ASO에 의해 제공되는 100% 생존 이점을 입증하는 예시적인 생존 곡선이다. +/+는 WT 유전자형을 나타내고, +/-는 129S-scn1atm1Kea 이형 접합 유전자형(드라벳 마우스 모델)을 나타내고; A는 PBS 처리를 나타내고, B는 ASO 처리를 나타낸다. 도시된 바와 같이, A +/- 그룹의 마우스(PBS 처리를 받은 드라벳 마우스)는 대략 생후 16일부터 죽기 시작했던 반면, B +/- 그룹(ASO 처리를 받은 드라벳 마우스)을 포함하는 다른 세 그룹의 모든 마우스는 적어도 생후 35일까지 생존하였다.
스플라이싱 및 넌센스 매개 mRNA 붕괴
개재 서열 또는 인트론은 스플라이스좀이라 불리는 크고 매우 역동적인 RNA-단백질 복합체에 의해 제거되며, 이는 1차 전사체, 작은 핵 RNA(snRNA) 및 다수의 단백질 사이의 복잡한 상호 작용을 조정한다. 스플라이스좀은 U1 snRNA에 의한 5' 스플라이스 부위(5'ss) 또는 U2 경로에 의한 3' 스플라이스 부위(3'ss)의 인식으로 시작하여, 순차적인 방식으로 각 인트론에 특별하게 조립되며, 이는 3'ss의 영역에 U2 보조 인자(U2AF)의 결합을 수반하여 분지점 서열(BPS: branch point sequence)에 U2 결합을 용이하게 한다. U2AF는 폴리피리미딘 트랙(PPT: polypyrimidine tract)에 결합하는 U2AF2-코딩된 65 kD 서브유닛(U2AF65), 및 3'ss에서 고도로 보존된 AG 디뉴클레오티드와 상호 작용하고 U2AF65 결합을 안정화시키는 U2AF1-코딩된 35 kD 서브유닛(U2AF35)으로 구성된 안정한 이종 이량체이다. 정확한 스플라이싱에는 BPS/PPT 유닛 및 3'ss/5'ss 외에도 인트론 또는 엑손 스플라이싱 인핸서 또는 사일런서로 알려진, 스플라이스 부위 인식을 활성화 또는 억제하는 보조 서열 또는 구조가 필요하다. 이들 요소는 동일한 서열을 갖지만 진짜 부위가 수십 배나 더 많은 고등 진핵 세포의 게놈에서 광대한 과량의 잠재 또는 가성(pseudo) 부위 중에서 진짜 스플라이스 부위를 인식할 수 있게 한다. 이들은 종종 조절 기능을 갖지만, 이들의 활성화 또는 억제의 정확한 메커니즘은 잘 이해되지 않고 있다.
스플라이스 여부에 대한 결정은 전형적으로 결정론적 과정보다는 확률론적 과정으로 모델링될 수 있어, 가장 결정적인 스플라이싱 신호조차 때때로 부정확하게 스플라이싱될 수 있다. 그러나 정상적인 조건하에서, 프리-mRNA 스플라이싱은 놀랍도록 높은 정확도로 진행된다. 이는 인접한 시스 작용 보조 엑손 및 인트론 스플라이싱 조절 요소(ESR 또는 ISR)의 활성에 부분적으로 기인한다. 전형적으로, 이들 기능적 요소는 스플라이싱을 자극하거나 억제하는 능력에 기초하여 각각 엑손 또는 인트론 스플라이싱 인핸서(ESE 또는 ISE) 또는 사일런서(ESS 또는 ISS)로 분류된다. 현재 일부 보조 시스 작용 요소가 U1 snRNP와 5'ss 사이의 복합체의 배열과 같은 스플라이스좀 어셈블리의 동역학에 영향을 미침으로써 작용할 수 있다는 증거가 있지만, 많은 요소는 트랜스 작용 RNA 결합 단백질(RBP)과 협력하여 기능을 할 가능성이 매우 크다. 예를 들어, 세린 및 아르기닌이 풍부한 RBP 패밀리(SR 단백질)는 엑손을 정의하는 데 중요한 역할을 하는 보존된 단백질 패밀리이다. SR 단백질은 프리-스플라이스좀의 성분을 인접한 스플라이스 부위로 동원하거나 근처에서 ESS의 효과를 길항함으로써 엑손 인식을 촉진한다. ESS의 억제 효과는 이종 핵 리보핵 단백질(hnRNP) 패밀리의 구성원에 의해 매개될 수 있으며, 인접 스플라이스 부위로의 코어 스플라이싱 인자의 동원을 변경할 수 있다. 스플라이싱 조절에서의 역할 외에도, 사일런서 요소는 전형적인 엑손 간격을 갖지만 기능적인 오픈 리딩 프레임이 없는 붕괴 인트론 스플라이스 부위 세트인 가성 엑손(pseudo exon)의 억제에 역할을 할 것으로 제안된다. ESE와 ESS는 동족 트랜스 작용 RBP와 협력하여 mRNA가 그들의 전구체로부터 언제, 어디서, 그리고 어떻게 조립되지를 지정하는 일련의 스플라이싱 제어에서 중요한 구성 요소를 나타낸다.
엑손-인트론 경계를 표시하는 서열은 인간 유전자 내에서 높은 빈도로 발생할 수 있는 다양한 강도의 축퇴성 신호이다. 다중 엑손 유전자에서, 상이한 쌍의 스플라이스 부위가 많은 상이한 조합으로 서로 연결되어 단일 유전자로부터 다양한 전사체를 생성할 수 있다. 이것을 일반적으로 선택적 프리-mRNA 스플라이싱이라고 한다. 선택적 스플라이싱에 의해 생성된 대부분의 mRNA 아이소형이 핵으로부터 유출되어 기능성 폴리펩티드로 번역될 수 있지만, 단일 유전자로부터의 상이한 mRNA 아이소형은 그들의 번역 효율이 크게 달라질 수 있다. 엑손 접합부 복합체의 적어도 50 bp 상류에 조기 종결 코돈(PTC: premature termination codon)을 갖는 mRNA 아이소형은 넌센스 매개 mRNA 붕괴(NMD) 경로에 의한 분해에 대해 표적화될 가능성이 있다. 전통적(BPS/PPT/3'ss/5'ss) 및 보조적 스플라이싱 모티프에서의 돌연변이는 엑손 스키핑 또는 잠재성(또는 가성) 엑손 포함 또는 스플라이스 부위 활성화와 같은 비정상적인 스플라이싱을 유발할 수 있으며, 인간 이환율 및 사망률에 상당한 원인이 된다. 비정상적 및 선택적 스플라이싱 양상은 둘 다 엑손 및 인트론에서의 천연 DNA 변이에 의해 영향받을 수 있다.
엑손-인트론 경계가 코돈의 3개 위치 중 어느 하나에서 발생할 수 있다고 가정하면, 선택적 스플라이싱 이벤트의 서브 세트만이 표준 오픈 리딩 프레임을 유지할 수 있다는 것은 명백하다. 예를 들어, 균등하게 3으로 나눌 수 있는 엑손만이 리딩 프레임을 변경하지 않고 스키핑되거나 mRNA에 포함될 수 있다. 적합한 상태가 없는 스플라이싱 이벤트는 프레임 시프트를 유발할 것이다. 하류 이벤트에 의해 역전되지 않는 한, 프레임 시프트는 확실히 하나 이상의 PTC로 이어질 수 있으며, 이는 아마도 NMD에 의한 후속 분해를 초래할 수 있다. NMD는 PTC를 함유하는 mRNA를 제거하는 번역 결합된 기전이다. NMD는 모든 진핵생물에 존재하는 감시 경로로서 기능을 할 수 있다. NMD는 조기 정지 코돈을 함유하는 mRNA 전사체를 제거함으로써 유전자 발현에서 오류를 감소시킬 수 있다. 이들 비정상적 mRNA의 번역은, 일부 경우에, 생성된 단백질의 유해한 기능 획득 또는 우성의 음성적 활성으로 이어질 수 있다. NMD는 PTC가 있는 전사체뿐 아니라 많은 내인성 유전자로부터 발현된 광범위한 mRNA 아이소형을 표적화하며, 이는 NMD가 세포의 정상 상태(steady-state) RNA 수준에서 미세 조정과 대충 조정을 모두 유도하는 마스터 조절 인자임을 시사한다.
NMD 유도 엑손(NIE)은 인트론 내의 영역인 엑손 또는 가성 엑손이며, 성숙한 RNA 전사체에 포함되는 경우 NMD 경로를 활성화시킬 수 있다. 구성적 스플라이싱 이벤트에서, NIE를 함유하는 인트론은 일반적으로 스플라이싱되지만, 인트론 또는 그 일부(예를 들어, NIE)는 선택적 또는 비정상적 스플라이싱 이벤트 중에 유지될 수 있다. 이러한 NIE를 함유하는 성숙한 mRNA 전사체는 NMD 경로를 유도하는 프레임 시프트로 인해 비생산적일 수 있다. 성숙한 RNA 전사체에 NIE가 포함되면 유전자 발현을 하향 조절할 수 있다. NIE를 함유하는 mRNA 전사체는 본 개시 내용에서 "NIE 함유 mRNA" 또는 "NMD 엑손 mRNA"로 지칭될 수 있다.
잠재성(또는 가성 스플라이스 부위)은 진짜 스플라이스 부위와 동일한 스플라이싱 인식 서열을 갖지만 스플라이싱 반응에는 사용되지 않는다. 이들은 인간 게놈에서 진짜 스플라이스 부위보다 수십 배 더 많으며 일반적으로 이렇게 잘 이해되지 않은 분자 기전에 의해 억제된다. 잠재성 5' 스플라이스 부위는 컨센서스 NNN/GUNNNN 또는 NNN/GCNNNN을 가지며, 여기서 N은 임의의 뉴클레오티드이고 엑손-인트론 경계이다. 잠재성 3' 스플라이스 부위는 컨센서스 NAG/N을 가진다. 이들의 활성화는 진짜 스플라이스 부위, 즉 각각 MAG/GURAGU 및 YAG/G(여기서 M은 C 또는 A, R은 G 또는 A, Y는 C 또는 U임)의 최적의 컨센서스와 더 유사하게 만드는 주변 뉴클레오티드에 의해 양성적으로 영향을 받는다.
스플라이스 부위 및 그의 조절 서열은 예를 들어, 문헌[Kralovicova, J. and Vorechovsky, I. (2007) Global control of aberrant splice site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition. Nucleic Acids Res., 35, 6399-6413,(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2095810/pdf/gkm680.pdf)]에 열거된 공개적으로 이용 가능한 적합한 알고리즘을 사용하여 당업자에 의해 용이하게 확인될 수 있다.
잠재성 스플라이스 부위 또는 스플라이싱 조절 서열은 U2AF와 같은 RNA 결합 단백질에 대해 NIE의 스플라이스 부위와 경쟁할 수 있다. 일 실시양태에서, 작용제는 잠재성 스플라이스 부위 또는 스플라이싱 조절 서열에 결합하여 RNA 결합 단백질의 결합을 방지함으로써 NIE 스플라이스 부위의 이용을 유리하게 할 수 있다.
일 실시양태에서, 잠재성 스플라이스 부위는 NIE의 5' 또는 3' 스플라이스 부위를 포함하지 않을 수 있다. 잠재성 스플라이스 부위는 NIE 5' 스플라이스 부위의 적어도 10 뉴클레오티드 상류에 있을 수 있다. 잠재성 스플라이스 부위는 NIE 5' 스플라이스 부위의 적어도 20 뉴클레오티드 상류에 있을 수 있다. 잠재성 스플라이스 부위는 NIE 5' 스플라이스 부위의 적어도 50 뉴클레오티드 상류에 있을 수 있다. 잠재성 스플라이스 부위는 NIE 5' 스플라이스 부위의 적어도 100 뉴클레오티드 상류에 있을 수 있다. 잠재성 스플라이스 부위는 NIE 5' 스플라이스 부위의 적어도 200 뉴클레오티드 상류에 있을 수 있다.
잠재성 스플라이스 부위는 NIE 3' 스플라이스 부위의 적어도 10 뉴클레오티드 하류에 있을 수 있다. 잠재성 스플라이스 부위는 NIE 3' 스플라이스 부위의 적어도 20 뉴클레오티드 하류에 있을 수 있다. 잠재성 스플라이스 부위는 NIE 3' 스플라이스 부위의 적어도 50 뉴클레오티드 하류에 있을 수 있다. 잠재성 스플라이스 부위는 NIE 3' 스플라이스 부위의 적어도 100 뉴클레오티드 하류에 있을 수 있다. 잠재성 스플라이스 부위는 NIE 3' 스플라이스 부위의 적어도 200 뉴클레오티드 하류에 있을 수 있다.
표적 전사체
일부 실시양태에서, 본 개시 내용의 방법은 SCN1A 유전자로부터 전사된 프리-mRNA에 NIE의 존재를 이용한다. 기능성 성숙 SCN1A mRNA를 생성하기 위한 확인된 SCN1A NIE 프리-mRNA 종의 스플라이싱은 NIE의 엑손 스키핑(exon skipping)을 자극하는 ASO와 같은 치료제를 사용하여 유도될 수 있다. 엑손 스키핑의 유도는 NMD 경로의 억제를 초래할 수 있다. 생성된 성숙한 SCN1A mRNA는 NMD 경로를 활성화시키지 않으면서 정상적으로 번역될 수 있으며, 이로써 환자 세포에서 SCN1A 단백질의 양을 증가시키고 SCN1A 결핍과 관련된 병태, 예를 들어 드라벳 증후군(DS); 열성 발작 플러스를 동반하는 전신 뇌전증 2형; 가족성 열성 발작 3A; 자폐증; 조기 유아 간질성 뇌병증 13; 동기능 부전 증후군　1; 알츠하이머병; 또는 SUDEP의 증상을 완화시킨다.
다양한 실시양태에서, 본 개시 내용은 SCN1A mRNA 전사체를 표적화하여, 스플라이싱 또는 단백질 발현 수준을 조절, 예를 들어, 향상 또는 억제할 수 있는 치료제를 제공한다. 치료제는 소분자, 폴리뉴클레오티드, 또는 폴리펩티드일 수 있다. 일부 실시양태에서, 치료제는 ASO이다. SCN1A 프리-mRNA 상의 다양한 영역 또는 서열이 ASO와 같은 치료제에 의해 표적화될 수 있다. 일부 실시양태에서, ASO는 NIE를 함유하는 SCN1A 프리-mRNA 전사체를 표적화한다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA 전사체의 NIE 내의 서열을 표적화한다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA 전사체의 NIE의 5' 말단으로부터 상류(또는 5') 서열(3'ss)을 표적화한다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA 전사체의 NIE의 3' 말단으로부터 하류(또는 3') 서열(5'ss)을 표적화한다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA 전사체의 NIE의 5' 말단의 측면에 위치한 인트론 내에 있는 서열을 표적화한다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA 전사체의 NIE의 3' 말단의 측면에 위치한 인트론 내에 있는 서열을 표적화한다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA 전사체의 NIE-인트론 경계를 포함하는 서열을 표적화한다. NIE-인트론 경계는 인트론 서열과 NIE 영역의 접합부를 지칭할 수 있다. 인트론 서열은 NIE의 5' 말단, 또는 NIE의 3' 말단의 측면에 위치할 수 있다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA 전사체의 엑손 내의 서열을 표적화한다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA 전사체의 인트론 내의 서열을 표적화한다. 일부 실시양태에서, ASO는 인트론의 일부 및 엑손의 일부를 둘 다 포함하는 서열을 표적화한다.
일부 실시양태에서, 본원에 기재된 치료제는 NMD 엑손 mRNA의 스플라이싱에 관여하는 인자의 결합을 조절한다.
일부 실시양태에서, 본원에 기재된 치료제는 NMD 엑손 mRNA의 스플라이싱에 관여하는 인자의 결합을 방해한다.
일부 실시양태에서, 본원에 기재된 치료제는 NMD 엑손 mRNA의 스플라이싱에 관여하는 인자의 결합을 방지한다.
일부 실시양태에서, 치료제는 SCN1A를 코딩하는 NMD 엑손 mRNA의 2개의 표준 엑손 영역 사이의 인트론 영역에 위치한 표적화된 부분을 표적화하며, 여기서 인트론 영역은 NMD 엑손을 함유한다.
일부 실시양태에서, 치료제는 NMD 엑손과 적어도 부분적으로 중첩되는 표적화된 부분을 표적화한다.
일부 실시양태에서, 치료제는 NMD 엑손의 상류 인트론과 적어도 부분적으로 중첩되는 표적화된 부분을 표적화한다.
일부 실시양태에서, 치료제는 NMD 엑손 내의 표적화된 부분을 표적화한다.
일부 실시양태에서, 치료제는 NMD 엑손의 적어도 약 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30개 또는 그 이상의 연속적인 뉴클레오티드를 포함하는 표적화된 부분을 표적화한다. 일부 실시양태에서, 치료제는 NMD 엑손의 최대 약 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30개 또는 그 이상의 연속적인 뉴클레오티드를 포함하는 표적화된 부분을 표적화한다. 일부 실시양태에서, 치료제는 NMD 엑손의 약 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30개 또는 그 이상의 연속적인 뉴클레오티드를 포함하는 표적화된 부분을 표적화한다.
일부 실시양태에서, 치료제는 NMD 엑손에 근접한 표적화된 부분을 표적화한다.
일부 실시양태에서, ASO는 NIE의 5' 말단으로부터 약 4 내지 약 300 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE 영역의 5' 말단으로부터 약 1 내지 약 20 뉴클레오티드, 약 20 내지 약 50 뉴클레오티드, 약 50 내지 약 100 뉴클레오티드, 약 100 내지 약 150 뉴클레오티드, 약 150 내지 약 200 뉴클레오티드, 약 200 내지 약 250 뉴클레오티드, 약 250 내지 약 300 뉴클레오티드, 약 350 내지 약 400 뉴클레오티드, 약 450 내지 약 500 뉴클레오티드, 약 550 내지 약 600 뉴클레오티드, 약 650 내지 약 700 뉴클레오티드, 약 750 내지 약 800 뉴클레오티드, 약 850 내지 약 900 뉴클레오티드, 약 950 내지 약 1000 뉴클레오티드, 약 1050 내지 약 1100 뉴클레오티드, 약 1150 내지 약 1200 뉴클레오티드, 약 1250 내지 약 1300 뉴클레오티드, 약 1350 내지 약 1400 뉴클레오티드, 또는 약 1450 내지 약 1500 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE의 5' 말단으로부터 300 뉴클레오티드 초과 상류의 서열을 표적화할 수 있다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 약 4 내지 약 300 뉴클레오티드 하류(또는 3')의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 약 1 내지 약 20 뉴클레오티드, 약 20 내지 약 50 뉴클레오티드, 약 50 내지 약 100 뉴클레오티드, 약 100 내지 약 150 뉴클레오티드, 약 150 내지 약 200 뉴클레오티드, 약 200 내지 약 250 뉴클레오티드, 약 250 내지 약 300 뉴클레오티드, 약 350 내지 약 400 뉴클레오티드, 약 450 내지 약 500 뉴클레오티드, 약 550 내지 약 600 뉴클레오티드, 약 650 내지 약 700 뉴클레오티드, 약 750 내지 약 800 뉴클레오티드, 약 850 내지 약 900 뉴클레오티드, 약 950 내지 약 1000 뉴클레오티드, 약 1050 내지 약 1100 뉴클레오티드, 약 1150 내지 약 1200 뉴클레오티드, 약 1250 내지 약 1300 뉴클레오티드, 약 1350 내지 약 1400 뉴클레오티드, 또는 약 1450 내지 약 1500 뉴클레오티드 하류의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 300 뉴클레오티드 초과 하류의 서열을 표적화한다.
일부 실시양태에서, ASO는 NIE의 5' 말단으로부터 약 4 내지 약 300 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO은 NIE 영역의 5' 말단으로부터 적어도 약 1 뉴클레오티드, 적어도 약 10 뉴클레오티드, 적어도 약 20 뉴클레오티드, 적어도 약 50 뉴클레오티드, 적어도 약 80 뉴클레오티드, 적어도 약 85 뉴클레오티드, 적어도 약 90 뉴클레오티드, 적어도 약 95 뉴클레오티드, 적어도 약 96 뉴클레오티드, 적어도 약 97 뉴클레오티드, 적어도 약 98 뉴클레오티드, 적어도 약 99 뉴클레오티드, 적어도 약 100 뉴클레오티드, 적어도 약 101 뉴클레오티드, 적어도 약 102 뉴클레오티드, 적어도 약 103 뉴클레오티드, 적어도 약 104 뉴클레오티드, 적어도 약 105 뉴클레오티드, 적어도 약 110 뉴클레오티드, 적어도 약 120 뉴클레오티드, 적어도 약 150 뉴클레오티드, 적어도 약 200 뉴클레오티드, 적어도 약 300 뉴클레오티드, 적어도 약 400 뉴클레오티드, 적어도 약 500 뉴클레오티드, 적어도 약 600 뉴클레오티드, 적어도 약 700 뉴클레오티드, 적어도 약 800 뉴클레오티드, 적어도 약 900 뉴클레오티드, 또는 적어도 약 1000 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 약 4 내지 약 300 뉴클레오티드 하류(또는 3')의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 적어도 약 1 뉴클레오티드, 적어도 약 10 뉴클레오티드, 적어도 약 20 뉴클레오티드, 적어도 약 50 뉴클레오티드, 적어도 약 80 뉴클레오티드, 적어도 약 85 뉴클레오티드, 적어도 약 90 뉴클레오티드, 적어도 약 95 뉴클레오티드, 적어도 약 96 뉴클레오티드, 적어도 약 97 뉴클레오티드, 적어도 약 98 뉴클레오티드, 적어도 약 99 뉴클레오티드, 적어도 약 100 뉴클레오티드, 적어도 약 101 뉴클레오티드, 적어도 약 102 뉴클레오티드, 적어도 약 103 뉴클레오티드, 적어도 약 104 뉴클레오티드, 적어도 약 105 뉴클레오티드, 적어도 약 110 뉴클레오티드, 적어도 약 120 뉴클레오티드, 적어도 약 150 뉴클레오티드, 적어도 약 200 뉴클레오티드, 적어도 약 300 뉴클레오티드, 적어도 약 400 뉴클레오티드, 적어도 약 500 뉴클레오티드, 적어도 약 600 뉴클레오티드, 적어도 약 700 뉴클레오티드, 적어도 약 800 뉴클레오티드, 적어도 약 900 뉴클레오티드, 또는 적어도 약 1000 뉴클레오티드 하류의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 300 뉴클레오티드 초과 하류의 서열을 표적화한다.
일부 실시양태에서, ASO는 NIE의 5' 말단으로부터 약 4 내지 약 300 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE 영역의 5' 말단으로부터 최대 약 10 뉴클레오티드, 최대 약 20 뉴클레오티드, 최대 약 50 뉴클레오티드, 최대 약 80 뉴클레오티드, 최대 약 85 뉴클레오티드, 최대 약 90 뉴클레오티드, 최대 약 95 뉴클레오티드, 최대 약 96 뉴클레오티드, 최대 약 97 뉴클레오티드, 최대 약 98 뉴클레오티드, 최대 약 99 뉴클레오티드, 최대 약 100 뉴클레오티드, 최대 약 101 뉴클레오티드, 최대 약 102 뉴클레오티드, 최대 약 103 뉴클레오티드, 최대 약 104 뉴클레오티드, 최대 약 105 뉴클레오티드, 최대 약 110 뉴클레오티드, 최대 약 120 뉴클레오티드, 최대 약 150 뉴클레오티드, 최대 약 200 뉴클레오티드, 최대 약 300 뉴클레오티드, 최대 약 400 뉴클레오티드, 최대 약 500 뉴클레오티드, 최대 약 600 뉴클레오티드, 최대 약 700 뉴클레오티드, 최대 약 800 뉴클레오티드, 최대 약 900 뉴클레오티드, 최대 약 1000 뉴클레오티드, 최대 약 1100 뉴클레오티드, 최대 약 1200 뉴클레오티드, 최대 약 1300 뉴클레오티드, 최대 약 1400 뉴클레오티드, 또는 최대 약 1500 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 약 4 내지 약 300 뉴클레오티드 하류(또는 3')의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 최대 약 10 뉴클레오티드, 최대 약 20 뉴클레오티드, 최대 약 50 뉴클레오티드, 최대 약 80 뉴클레오티드, 최대 약 85 뉴클레오티드, 최대 약 90 뉴클레오티드, 최대 약 95 뉴클레오티드, 최대 약 96 뉴클레오티드, 최대 약 97 뉴클레오티드, 최대 약 98 뉴클레오티드, 최대 약 99 뉴클레오티드, 최대 약 100 뉴클레오티드, 최대 약 101 뉴클레오티드, 최대 약 102 뉴클레오티드, 최대 약 103 뉴클레오티드, 최대 약 104 뉴클레오티드, 최대 약 105 뉴클레오티드, 최대 약 110 뉴클레오티드, 최대 약 120 뉴클레오티드, 최대 약 150 뉴클레오티드, 최대 약 200 뉴클레오티드, 최대 약 300 뉴클레오티드, 최대 약 400 뉴클레오티드, 최대 약 500 뉴클레오티드, 최대 약 600 뉴클레오티드, 최대 약 700 뉴클레오티드, 최대 약 800 뉴클레오티드, 최대 약 900 뉴클레오티드, 또는 최대 약 1000 뉴클레오티드, 최대 약 1100 뉴클레오티드, 최대 약 1200 뉴클레오티드, 최대 약 1300 뉴클레오티드, 최대 약 1400 뉴클레오티드, 또는 최대 약 1500 뉴클레오티드 하류의 서열을 표적화한다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 300 뉴클레오티드 초과 하류의 서열을 표적화한다.
일부 실시양태에서, 본원에 기재된 바와 같은 NIE는 [도 2]에 도시된 바와 같이 GRCh37/hg19: chr2:166,863,740과 GRCh37/hg19: chr2:166,863,803 사이에 위치한다. 일부 실시양태에서, NIE의 5' 말단은 GRCh37/hg19: chr2:166,863,803에 위치한다. 일부 실시양태에서, NIE의 3' 말단은 GRCh37/hg19: chr2:166,863,740에 위치한다.
일부 실시양태에서, ASO는 게놈 부위 GRCh37/hg19: chr2:166,863,803으로부터 약 4 내지 약 300 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 게놈 부위 GRCh37/hg19: chr2:166,863,803으로부터 약 1 내지 약 20 뉴클레오티드, 약 20 내지 약 50 뉴클레오티드, 약 50 내지 약 100 뉴클레오티드, 약 100 내지 약 150 뉴클레오티드, 약 150 내지 약 200 뉴클레오티드, 약 200 내지 약 250 뉴클레오티드, 약 250 내지 약 300, 약 250 내지 약 300 뉴클레오티드, 약 350 내지 약 400 뉴클레오티드, 약 450 내지 약 500 뉴클레오티드, 약 550 내지 약 600 뉴클레오티드, 약 650 내지 약 700 뉴클레오티드, 약 750 내지 약 800 뉴클레오티드, 약 850 내지 약 900 뉴클레오티드, 약 950 내지 약 1000 뉴클레오티드, 약 1050 내지 약 1100 뉴클레오티드, 약 1150 내지 약 1200 뉴클레오티드, 약 1250 내지 약 1300 뉴클레오티드, 약 1350 내지 약 1400 뉴클레오티드, 또는 약 1450 내지 약 1500 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 게놈 부위 GRCh37/hg19: chr2:166,863,803으로부터 300 뉴클레오티드 초과 상류의 서열을 표적화할 수 있다. 일부 실시양태에서, ASO는 GRCh37/hg19: chr2:166,863,740으로부터 약 4 내지 약 300 뉴클레오티드 하류(또는 3')의 서열을 표적화한다. 일부 실시양태에서, ASO는 GRCh37/hg19: chr2:166,863,740으로부터 약 1 내지 약 20 뉴클레오티드, 약 20 내지 약 50 뉴클레오티드, 약 50 내지 약 100 뉴클레오티드, 약 100 내지 약 150 뉴클레오티드, 약 150 내지 약 200 뉴클레오티드, 약 200 내지 약 250 뉴클레오티드, 약 250 내지 약 300 뉴클레오티드, 약 350 내지 약 400 뉴클레오티드, 약 450 내지 약 500 뉴클레오티드, 약 550 내지 약 600 뉴클레오티드, 약 650 내지 약 700 뉴클레오티드, 약 750 내지 약 800 뉴클레오티드, 약 850 내지 약 900 뉴클레오티드, 약 950 내지 약 1000 뉴클레오티드, 약 1050 내지 약 1100 뉴클레오티드, 약 1150 내지 약 1200 뉴클레오티드, 약 1250 내지 약 1300 뉴클레오티드, 약 1350 내지 약 1400 뉴클레오티드, 또는 약 1450 내지 약 1500 뉴클레오티드 하류의 서열을 표적화한다. 일부 실시양태에서, ASO는 GRCh37/hg19: chr2:166,863,740으로부터 300 뉴클레오티드 초과 하류의 서열을 표적화한다.
일부 실시양태에서, ASO는 게놈 부위 GRCh37/hg19: chr2:166,863,803으로부터 약 4 내지 약 300 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 게놈 부위 GRCh37/hg19: chr2:166,863,803으로부터 적어도 약 1 뉴클레오티드, 적어도 약 10 뉴클레오티드, 적어도 약 20 뉴클레오티드, 적어도 약 50 뉴클레오티드, 적어도 약 80 뉴클레오티드, 적어도 약 85 뉴클레오티드, 적어도 약 90 뉴클레오티드, 적어도 약 95 뉴클레오티드, 적어도 약 96 뉴클레오티드, 적어도 약 97 뉴클레오티드, 적어도 약 98 뉴클레오티드, 적어도 약 99 뉴클레오티드, 적어도 약 100 뉴클레오티드, 적어도 약 101 뉴클레오티드, 적어도 약 102 뉴클레오티드, 적어도 약 103 뉴클레오티드, 적어도 약 104 뉴클레오티드, 적어도 약 105 뉴클레오티드, 적어도 약 110 뉴클레오티드, 적어도 약 120 뉴클레오티드, 적어도 약 150 뉴클레오티드, 적어도 약 200 뉴클레오티드, 적어도 약 300 뉴클레오티드, 적어도 약 400 뉴클레오티드, 적어도 약 500 뉴클레오티드, 적어도 약 600 뉴클레오티드, 적어도 약 700 뉴클레오티드, 적어도 약 800 뉴클레오티드, 적어도 약 900 뉴클레오티드, 또는 적어도 약 1000 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 GRCh37/hg19: chr2:166,863,740으로부터 약 4 내지 약 300 뉴클레오티드 하류(또는 3')의 서열을 표적화한다. 일부 실시양태에서, ASO는 GRCh37/hg19: chr2:166,863,740으로부터 적어도 약 1 뉴클레오티드, 적어도 약 10 뉴클레오티드, 적어도 약 20 뉴클레오티드, 적어도 약 50 뉴클레오티드, 적어도 약 80 뉴클레오티드, 적어도 약 85 뉴클레오티드, 적어도 약 90 뉴클레오티드, 적어도 약 95 뉴클레오티드, 적어도 약 96 뉴클레오티드, 적어도 약 97 뉴클레오티드, 적어도 약 98 뉴클레오티드, 적어도 약 99 뉴클레오티드, 적어도 약 100 뉴클레오티드, 적어도 약 101 뉴클레오티드, 적어도 약 102 뉴클레오티드, 적어도 약 103 뉴클레오티드, 적어도 약 104 뉴클레오티드, 적어도 약 105 뉴클레오티드, 적어도 약 110 뉴클레오티드, 적어도 약 120 뉴클레오티드, 적어도 약 150 뉴클레오티드, 적어도 약 200 뉴클레오티드, 적어도 약 300 뉴클레오티드, 적어도 약 400 뉴클레오티드, 적어도 약 500 뉴클레오티드, 적어도 약 600 뉴클레오티드, 적어도 약 700 뉴클레오티드, 적어도 약 800 뉴클레오티드, 적어도 약 900 뉴클레오티드, 또는 적어도 약 1000 뉴클레오티드 하류의 서열을 표적화한다. 일부 실시양태에서, ASO는 GRCh37/hg19: chr2:166,863,740으로부터 300 뉴클레오티드 초과 하류의 서열을 표적화한다.
일부 실시양태에서, ASO는 게놈 부위 GRCh37/hg19: chr2:166,863,803으로부터 약 4 내지 약 300 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 게놈 부위 GRCh37/hg19: chr2:166,863,803으로부터 최대 약 10 뉴클레오티드, 최대 약 20 뉴클레오티드, 최대 약 50 뉴클레오티드, 최대 약 80 뉴클레오티드, 최대 약 85 뉴클레오티드, 최대 약 90 뉴클레오티드, 최대 약 95 뉴클레오티드, 최대 약 96 뉴클레오티드, 최대 약 97 뉴클레오티드, 최대 약 98 뉴클레오티드, 최대 약 99 뉴클레오티드, 최대 약 100 뉴클레오티드, 최대 약 101 뉴클레오티드, 최대 약 102 뉴클레오티드, 최대 약 103 뉴클레오티드, 최대 약 104 뉴클레오티드, 최대 약 105 뉴클레오티드, 최대 약 110 뉴클레오티드, 최대 약 120 뉴클레오티드, 최대 약 150 뉴클레오티드, 최대 약 200 뉴클레오티드, 최대 약 300 뉴클레오티드, 최대 약 400 뉴클레오티드, 최대 약 500 뉴클레오티드, 최대 약 600 뉴클레오티드, 최대 약 700 뉴클레오티드, 최대 약 800 뉴클레오티드, 최대 약 900 뉴클레오티드, 최대 약 1000 뉴클레오티드, 최대 약 1100 뉴클레오티드, 최대 약 1200 뉴클레오티드, 최대 약 1300 뉴클레오티드, 최대 약 1400 뉴클레오티드, 또는 최대 약 1500 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 GRCh37/hg19: chr2:166,863,740으로부터 약 4 내지 약 300 뉴클레오티드 하류(또는 3')의 서열을 표적화한다. 일부 실시양태에서, ASO는 GRCh37/hg19: chr2:166,863,740으로부터 최대 약 10 뉴클레오티드, 최대 약 20 뉴클레오티드, 최대 약 50 뉴클레오티드, 최대 약 80 뉴클레오티드, 최대 약 85 뉴클레오티드, 최대 약 90 뉴클레오티드, 최대 약 95 뉴클레오티드, 최대 약 96 뉴클레오티드, 최대 약 97 뉴클레오티드, 최대 약 98 뉴클레오티드, 최대 약 99 뉴클레오티드, 최대 약 100 뉴클레오티드, 최대 약 101 뉴클레오티드, 최대 약 102 뉴클레오티드, 최대 약 103 뉴클레오티드, 최대 약 104 뉴클레오티드, 최대 약 105 뉴클레오티드, 최대 약 110 뉴클레오티드, 최대 약 120 뉴클레오티드, 최대 약 150 뉴클레오티드, 최대 약 200 뉴클레오티드, 최대 약 300 뉴클레오티드, 최대 약 400 뉴클레오티드, 최대 약 500 뉴클레오티드, 최대 약 600 뉴클레오티드, 최대 약 700 뉴클레오티드, 최대 약 800 뉴클레오티드, 최대 약 900 뉴클레오티드, 또는 최대 약 1000 뉴클레오티드, 최대 약 1100 뉴클레오티드, 최대 약 1200 뉴클레오티드, 최대 약 1300 뉴클레오티드, 최대 약 1400 뉴클레오티드, 또는 최대 약 1500 뉴클레오티드 하류의 서열을 표적화한다. 일부 실시양태에서, ASO는 GRCh37/hg19: chr2:166,863,740으로부터 300 뉴클레오티드 초과 하류의 서열을 표적화한다.
본원에서 실시예에 기재된 바와 같이, SCN1A 유전자(서열 번호 1)를 NIE에 대해 분석하고 인트론 20의 일부(서열 번호 4)의 포함이 관찰되었다(이 부분은 본 개시 내용 전체에 걸쳐 엑손 20x로 지칭됨). 일부 실시양태에서, 본원에 개시된 ASO는 SCN1A 게놈 서열로부터 전사된 NIE 함유 프리-mRNA(서열 번호 2)를 표적화한다. 일부 실시양태에서, ASO는 인트론 20의 일부를 포함하는 SCN1A 게놈 서열로부터의 NIE 함유 프리-mRNA 전사체를 표적화한다. 일부 실시양태에서, ASO는 엑손 20x(서열 번호 6)를 포함하는 SCN1A 게놈 서열로부터의 NIE 함유 프리-mRNA 전사체를 표적화한다. 일부 실시양태에서, ASO는 서열 번호 2 또는 12의 NIE 함유 프리-mRNA 전사체를 표적화한다. 일부 실시양태에서, ASO는 NIE를 포함하는 서열 번호 2 또는 12의 프리-mRNA 전사체를 표적화한다. 일부 실시양태에서, ASO는 엑손 20x을 포함하는 서열 번호 2의 NIE 함유 프리-mRNA 전사체(서열 번호 10)를 표적화한다. 일부 실시양태에서, 본원에 개시된 ASO는 SCN1A 프리-mRNA 서열(서열 번호 2 또는 12)을 표적화한다. 일부 실시양태에서, ASO는 NIE를 포함하는 SCN1A 프리-mRNA 서열(서열 번호 10 또는 20)을 표적화한다. 일부 실시양태에서, ASO는 서열 번호 7 내지 10 또는 17 내지 20 중 어느 하나에 따른 SCN1A 프리-mRNA 서열을 표적화한다. 일부 실시양태에서, ASO는 서열 번호 21 내지 67 중 어느 하나에 따른 서열을 갖는다. 일부 실시양태에서, ASO는 서열 번호 68 내지 114 중 어느 하나에 따른 서열을 갖는다. 일부 실시양태에서, ASO는 서열 번호 115 내지 209 중 어느 하나에 따른 서열을 갖는다. 일부 실시양태에서, ASO는 서열 번호 210 내지 256 중 어느 하나에 따른 서열을 갖는다. 일부 실시양태에서, ASO는 서열 번호 257 내지 303 중 어느 하나에 따른 서열을 갖는다. 일부 실시양태에서, ASO는 서열 번호 304 내지 341 중 어느 하나에 따른 서열을 갖는다. 일부 실시양태에서, ASO는 서열 번호 342 내지 379 중 어느 하나에 따른 서열을 갖는다.
일부 실시양태에서, SCN1A NIE 함유 프리-mRNA 전사체는 서열 번호 1 또는 11과 적어도 약 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 서열 동일성을 갖는 유전자 서열에 의해 코딩된다. 일부 실시양태에서, SCN1A NIE 프리-mRNA 전사체는 서열 번호 2 내지 10 및 12 내지 20 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 서열 동일성을 갖는 서열을 포함한다.
일부 실시양태에서, SCN1A NIE 함유 프리-mRNA 전사체(또는 NMD 엑손 mRNA)는 서열 번호 2, 7 내지 10, 12 및 17 내지 20 중 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함한다. 일부 실시양태에서, SCN1A NIE 함유 프리-mRNA 전사체(또는 NMD 엑손 mRNA)은 서열 번호 1, 3 내지 6, 11, 및 13 내지 16과 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열에 의해 코딩된다. 일부 실시양태에서, NMD 엑손 mRNA의 표적화된 부분은 서열 번호 2, 7 내지 10, 12, 및 17 내지 20의 적어도 8개의 인접한 핵산을 포함하는 영역과 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함한다.
일부 실시양태에서, ASO는 NIE 엑손 20x를 포함하는 SCN1A NIE 함유 프리-mRNA의 엑손 20을 표적화한다. 일부 실시양태에서, ASO는 NIE 엑손 20x의 하류(또는 3')의 엑손 21 서열을 표적화한다. 일부 실시양태에서, ASO는 엑손 20x의 5' 말단으로부터 약 4 내지 약 300 뉴클레오티드 상류(또는 5')의 서열을 표적화한다. 일부 실시양태에서, ASO는 엑손 20x의 3' 말단으로부터 약 4 내지 약 300 뉴클레오티드 하류(또는 3')의 서열을 표적화한다. 일부 실시양태에서, ASO는 서열 번호 21 내지 67 중 어느 하나에 따른 서열을 갖는다. 일부 실시양태에서, ASO는 서열 번호 210 내지 256 중 어느 하나에 따른 서열을 갖는다.
일부 실시양태에서, ASO는 NIE의 5' 말단으로부터 상류 서열을 표적화한다. 예를 들어, NIE(예를 들어, 인간 SCN1A에서 엑손 20x, 또는 마우스 SCN1A에서 엑손 21x)의 5' 말단으로부터 상류 서열을 표적화하는 ASO는 서열 번호 21 내지 38 중 어느 하나와 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함할 수 있다. 다른 예에서, NIE(예를 들어, 인간 SCN1A에서 엑손 20x, 또는 마우스 SCN1A에서 엑손 21x)의 5' 말단으로부터 상류 서열을 표적화하는 ASO는 서열 번호 68 내지 85 중 어느 하나와 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함할 수 있다. 일부 실시양태에서, ASO는 엑손-인트론 경계(또는 접합부)를 함유하는 서열을 표적화한다. 예를 들어, 엑손-인트론 경계를 함유하는 서열을 표적화하는 ASO는 서열 번호 39 내지 41, 51, 52, 228 내지 230, 240, 또는 241 중 어느 하나와 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함할 수 있다. 다른 예에서, 엑손-인트론 경계를 함유하는 서열을 표적화하는 ASO는 서열 번호 86 내지 88 및 98 내지 99 중 어느 하나와 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함할 수 있다. 일부 실시양태에서, ASO는 NIE의 3' 말단으로부터 하류 서열을 표적화한다. 예를 들어, NIE(예를 들어, 인간 SCN1A에서 엑손 20x, 또는 마우스 SCN1A에서 엑손 21x)의 3' 말단으로부터 하류 서열을 표적화하는 ASO는 서열 번호 53 내지 67 중 어느 하나와 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함할 수 있다. 다른 예에서, NIE(예를 들어, 인간 SCN1A에서 엑손 20x, 또는 마우스 SCN1A에서 엑손 21x)의 3' 말단으로부터 하류 서열을 표적화하는 ASO는 서열 번호 100 내지 114 중 어느 하나와 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함할 수 있다. 일부 실시양태에서, ASO는 NIE 내의 서열을 표적화한다. 일부 실시양태에서, NIE(예를 들어, 인간 SCN1A에서 엑손 20x, 또는 마우스 SCN1A에서 엑손 21x) 내의 서열을 표적화하는 ASO는 서열 번호 42 내지 50, 또는 231 내지 239 중 어느 하나와 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함할 수 있다. 다른 예에서, NIE(예를 들어, 인간 SCN1A에서 엑손 20x, 또는 마우스 SCN1A에서 엑손 21x) 내의 서열을 표적화하는 ASO는 서열 번호 89 내지 97 중 어느 하나와 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함할 수 있다.
일부 실시양태에서, ASO는 엑손 20x를 포함하는 SCN1A NIE 함유 프리-mRNA에서 엑손 20x를 표적화한다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA의 엑손 20x의 5' 말단으로부터 하류(또는 3')의 엑손 20x 서열을 표적화한다. 일부 실시양태에서, ASO는 SCN1A 프리-mRNA의 엑손 20x의 3' 말단으로부터 상류(또는 5')의 엑손 20x 서열을 표적화한다.
일부 실시양태에서, SCN1A NIE 함유 프리-mRNA의 표적화된 부분은 인트론 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 또는 25(NM_006920에서 mRNA 서열에 상응하는 인트론 넘버링)에 있다. 일부 실시양태에서, NIE 프리-mRNA의 표적화된 부분에 대한 ASO의 혼성화는 인트론 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 또는 25 내의 하나 이상의 NIE의 엑손 스키핑을 초래하고, 계속하여 SCN1A 단백질 생산을 증가시킨다. 일부 실시양태에서, NIE 프리-mRNA의 표적화된 부분에 대한 ASO의 혼성화는 인트론 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 또는 25 내의 하나 이상의 NIE의 엑손 스키핑을 억제 또는 차단하고, 계속하여 SCN1A 단백질 생산을 감소시킨다. 일부 실시양태에서, SCN1A NIE 함유 프리-mRNA의 표적화된 부분은 인트론 20에 있다. 당업자는 본원에 제공된 인트론 서열에 기초하여 또는 NM_006920, NM_001202435, NM_001165964, 또는 NM_001165963에서 mRNA 서열과 관련하여 제공된 인트론 번호를 사용하여, 임의의 SCN1A 아이소형에서 상응하는 인트론 번호를 결정할 수 있다. 당업자는 또한 본원에 제공된 인트론 서열에 기초하여 또는 NM_006920, NM_001202435, NM_001165964, 또는 NM_001165963에서 mRNA 서열을 관련하여 제공된 인트론 번호를 사용하여, 본 발명의 방법을 사용하여 표적화하기 위한 임의의 SCN1A 아이소형에서 측면에 위치한 엑손의 서열을 결정할 수 있다.
일부 실시양태에서, 본 개시 내용의 방법 및 조성물은 SCN1A NIE 함유 프리-mRNA의 가성 엑손의 엑손 스키핑을 유도하거나 억제함으로써 SCN1A의 발현을 조절, 예를 들어, 증가 또는 감소시키는 데 사용된다. 일부 실시양태에서, 가성 엑손은 인트론 1 내지 25 중 어느 하나 내의 서열이다. 일부 실시양태에서, 가성 엑손은 인트론 2, 4, 6, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 및 25 중 어느 하나 내의 서열이다. 가성 엑손은 인트론 15, 18, 및 19 중 어느 하나 내의 서열이다. 일부 실시양태에서, 가성 엑손은 임의의 SCN1A 인트론 또는 이의 일부일 수 있다. 일부 실시양태에서, 가성 엑손은 인트론 20 내에 있다. 본원에 사용된 SCN1A 인트론 넘버링은 NM_006920에서의 mRNA 서열에 상응한다. 인트론 넘버링은 상이한 SCN1A 아이소형 서열과 관련하여 변할 수 있는 것으로 이해된다.
SCN1A 단백질
SCN1A 유전자는 SCN1A(나트륨 채널, 전압-게이팅, I형, 알파 서브유닛) 단백질을 코딩할 수 있으며, 이는 또한 전압-게이팅 나트륨 채널 Nav1.1의 알파-서브유닛으로 지칭될 수 있다. 또한, 전술한 바와 같이, DS에서 SCN1A 돌연변이는 전체 단백질에 걸쳐 퍼져있다. 데 노보(de novo) 발생이 더 약화된 100개 초과의 신규 돌연변이가 유전자 전체에 걸쳐 확인되었다. 이들은 절두(47%), 미스센스(43%), 결실(3%), 및 스플라이스 부위 돌연변이(7%)로 구성된다. SCN1A 돌연변이를 갖는 대상체의 백분율은 33 내지 100%로 다양하다. 대부분의 돌연변이는 신규 변화(88%)이다.
일부 실시양태에서, 본원에 기재된 방법은 기능성 SCN1A 단백질의 생산을 조절, 예를 들어 증가 또는 감소시키기 위해 사용된다. 본원에 사용된 바와 같이, 용어 "기능성"은 치료되는 병태, 예를 들어 드라벳 증후군; 열성 발작 플러스를 동반하는 전신 뇌전증 2형; 가족성 열성 발작 3A; 자폐증; 조기 유아 간질성 뇌병증 13; 동기능 부전 증후군　1; 알츠하이머병; 또는 SUDEP의 임의의 하나 이상의 증상을 제거하는데 필요한 양의 SCN1A 단백질 활성 또는 기능을 지칭한다. 일부 실시양태에서, 방법은 부분 기능성 SCN1A 단백질의 생산을 증가시키는 데 사용된다. 본원에 사용된 바와 같이, 용어 "부분 기능성"은 질환 또는 병태의 임의의 하나 이상의 증상을 제거 또는 예방하는데 필요한 양의 활성 또는 기능보다 적은 임의의 양의 SCN1A 단백질 활성 또는 기능을 지칭한다. 일부 실시양태에서, 부분 기능성 단백질 또는 RNA는 완전 기능성 단백질 또는 RNA와 비교하여 10% 이상, 20% 이상, 30% 이상, 40% 이상, 50% 이상, 60% 이상, 70% 이상, 75% 이상, 80% 이상, 85% 이상, 90% 이상, 또는 95% 이상 적은 활성을 가질 것이다.
일부 실시양태에서, 상기 방법은 SCN1A 단백질을 코딩하는 NIE 함유 프리-mRNA를 갖는 대상체의 세포에 의한 SCN1A 단백질의 발현을 증가시키는 방법으로서, 대상체는 결핍된 양의 SCN1A 단백질 활성에 의해 야기된 드라벳 증후군을 가지며, 결핍된 양의 SCN1A 단백질은 SCN1A 단백질의 반가불충분성에 의해 야기되는 것인 방법이다. 이러한 실시양태에서, 대상체는 기능성 SCN1A 단백질을 코딩하는 제1 대립 유전자, 및 SCN1A 단백질이 생성되지 않는 제2 대립 유전자를 갖는다. 이러한 또 다른 실시양태에서, 대상체는 기능성 SCN1A 단백질을 코딩하는 제1 대립 유전자, 및 비기능성 SCN1A 단백질을 코딩하는 제2 대립 유전자를 갖는다. 이러한 또 다른 실시양태에서, 대상체는 기능성 SCN1A 단백질을 코딩하는 제1 대립 유전자, 및 부분 기능성 SCN1A 단백질을 코딩하는 제2 대립 유전자를 갖는다. 이들 임의의 실시양태에서, 안티센스 올리고머는 제2 대립 유전자로부터 전사된 NIE 함유 프리-mRNA의 표적화된 부분에 결합함으로써 프리-mRNA로부터 가성 엑손의 엑손 스키핑을 유도하고, 대상체의 세포에서 기능성 SCN1A 단백질을 코딩하는 성숙한 mRNA의 수준 증가, 및 SCN1A 단백질의 발현 증가를 일으킨다.
관련 실시양태에서, 방법은 단백질 또는 기능성 RNA의 발현을 증가시키기 위해 ASO를 사용하는 방법이다. 일부 실시양태에서, ASO는 SCN1A 단백질을 코딩하는 NIE 함유 프리-mRNA를 갖는 대상체의 세포에서 SCN1A 단백질의 발현을 증가시키는 데 사용되며, 여기서 대상체는 SCN1A 단백질의 양 또는 기능에 있어 결핍증, 예를 들어 드라벳 증후군(DS)(SMEI로도 알려짐); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 동기능 부전 증후군 1; 조기 유아 SCN1A 뇌병증; 조기 유아 간질성 뇌병증(EIEE); 또는 자폐증을 갖는다. 일부 실시양태에서, ASO는 대상체의 세포에서 SCN1A 단백질의 발현을 증가시키는 데 사용되며, 여기서 대상체는 SCN8A 단백질의 양 또는 기능에 있어 결핍증, 예를 들어 조기 유아 간질성 뇌병증 13을 갖는다. 일부 실시양태에서, ASO는 대상체의 세포에서 SCN1A 단백질의 발현을 증가시키는 데 사용되며, 여기서 대상체는 SCN5A 단백질의 양 또는 기능에 있어 결핍증, 예를 들어 동기능 부전 증후군　1을 갖는다.
일부 실시양태에서, 질환 또는 병태를 유발하는 단백질을 코딩하는 NIE 함유 프리-mRNA 전사체는 본원에 기재된 ASO에 의해 표적화된다. 일부 실시양태에서, 질환을 유발하지 않는 단백질을 코딩하는 NIE 함유 프리-mRNA 전사체는 ASO에 의해 표적화된다. 예를 들어, 특정 경로에서 제1 단백질의 돌연변이 또는 결핍의 결과인 질환은 제2 단백질을 코딩하는 NIE 함유 프리-mRNA를 표적화함으로써 제2 단백질의 생성을 증가시켜 개선될 수 있다. 일부 실시양태에서, 제2 단백질의 기능은 (질환 또는 병태의 원인이 되는) 제1 단백질의 돌연변이 또는 결핍을 보상할 수 있다.
일부 실시양태에서, 대상체는
(a) (i) SCN1A 단백질이 야생형 대립 유전자로부터의 생산과 비교하여 감소한 수준으로 생성되거나,
(ii) SCN1A 단백질이 동등한 야생형 단백질과 비교하여 기능이 감소한 형태로 생성되거나,
(iii) SCN1A 단백질 또는 기능성 RNA가 생성되지 않는
제1 돌연변이 대립 유전자; 및
(b) (i) SCN1A 단백질이 야생형 대립 유전자로부터의 생산과 비교하여 감소한 수준으로 생성되거나,
(ii) SCN1A 단백질이 동등한 야생형 단백질과 비교하여 기능이 감소한 형태로 생성되거나,
(iii) SCN1A 단백질이 생성되지 않는
제2 돌연변이 대립 유전자를 가지며,
여기서 NIE 함유 프리-mRNA는 제1 대립 유전자 및/또는 제2 대립 유전자로부터 전사된다. 이들 실시양태에서, ASO는 제1 대립 유전자 또는 제2 대립 유전자로부터 전사된 NIE 함유 프리-mRNA의 표적화된 부분에 결합함으로써, NIE 함유 프리-mRNA로부터 가성 엑손의 엑손 스키핑을 유도하고, 대상체의 세포에서 SCN1A 단백질을 코딩하는 mRNA의 수준증가 및 표적 단백질 또는 기능성 RNA의 발현 증가를 일으킨다. 이들 실시양태에서, NIE 함유 프리-mRNA로부터의 가성 엑손의 엑손 스키핑으로 인한 발현 수준의 증가를 보이는 표적 단백질 또는 기능성 RNA는 동등한 야생형 단백질과 비교하여 기능이 감소한 형태(부분 기능성), 또는 동등한 야생형 단백질과 비교하여 완전한 기능을 보이는 형태(완전 기능성)이다.
일부 실시양태에서, SCN1A 단백질을 코딩하는 mRNA의 수준은 대조군 세포, 예를 들어 안티센스 올리고머로 처리되지 않은 것 또는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 결합하지 않는 안티센스 올리고머로 처리된 것에서 생성된 SCN1A 단백질을 코딩하는 mRNA의 양에 비해 1.1 내지 10배 증가한다.
일부 실시양태에서, 본 개시 내용의 방법을 사용하여 치료되는 대상체는 하나의 대립 유전자로부터 부분 기능성 SCN1A 단백질을 발현하며, 여기서 부분 기능성 SCN1A 단백질은 프레임 시프트 돌연변이, 넌센스 돌연변이, 미스센스 돌연변이, 또는 부분 유전자 결실에 의해 야기된다. 일부 실시양태에서, 본 발명의 방법을 사용하여 치료되는 대상체는 하나의 대립 유전자로부터 비기능성 SCN1A 단백질을 발현하며, 여기서 비기능성 SCN1A 단백질은 하나의 대립 유전자에서 프레임 시프트 돌연변이, 넌센스 돌연변이, 미스센스 돌연변이, 부분 유전자 결실에 의해 야기된다. 일부 실시양태에서, 본 발명의 방법을 사용하여 치료되는 대상체는 하나의 대립 유전자에서 SCN1A 전체 유전자 결실을 갖는다.
일부 실시양태에서, 상기 방법은 SCN1A 단백질을 코딩하는 NIE 함유 프리-mRNA를 갖는 대상체의 세포에 의한 SCN1A 단백질의 발현을 감소시키는 방법으로서, 대상체는 Nav1.1의 기능 획득 돌연변이를 갖는 것인 방법이다. 이러한 실시양태에서, 대상체는 SCN1A 단백질이 상승한 양으로 생성된 대립 유전자 또는 세포에서 Nav1.1의 증가한 활성을 유도하는 돌연변이 SCN1A를 코딩하는 대립 유전자를 갖는다. 일부 실시양태에서, Nav1.1의 증가한 활성은 돌연변이 Nav1.1 통로에 의해 매개되는 연장된 또는 거의 지속성의 나트륨 전류, 빠른 불활성화의 둔화, 정상 상태 불활성화의 양(positive)의 이동, 반복적인 자극 중에 높은 통로 이용 가능성, 비-불활성화된 탈분극-유도된 지속성의 나트륨 전류의 증가, 불활성화로의 진입 지연, 빠른 불활성화로부터의 회복 가속화, 및/또는 저온에서의 인큐베이션 또는 상호 작용 단백질의 공동-발현에 의한 폴딩 결함의 구제를 특징으로 한다. 이들 임의의 실시양태에서, 안티센스 올리고머는 제2 대립 유전자로부터 전사된 NIE 함유 프리-mRNA의 표적화된 부분에 결합함으로써 프리-mRNA로부터 가성 엑손의 엑손 스키핑을 억제 또는 차단하고, 대상체의 세포에서 기능성 SCN1A 단백질을 코딩하는 성숙한 mRNA의 수준 감소, 및 SCN1A 단백질의 발현 감소를 일으킨다.
관련 실시양태에서, 상기 방법은 단백질 또는 기능성 RNA의 발현을 감소시키기 위해 ASO를 사용하는 방법이다. 일부 실시양태에서, ASO는 SCN1A 단백질을 코딩하는 NIE 함유 프리-mRNA를 갖는 대상체의 세포에서 SCN1A 단백질의 발현을 감소시키는 데 사용된다. 일부 실시양태에서, 대상체는 Nav1.1의 기능 획득 돌연변이를 가지며, 예를 들어 편두통을 갖는다. 일부 실시양태에서, ASO는 대상체의 세포에서 SCN1A 단백질의 발현을 감소시키는 데 사용되며, 대상체는 Nav1.1의 기능 획득 돌연변이를 가지며, 예를 들어 가족성 편마비 편두통 3을 갖는다.
일부 실시양태에서, SCN1A 단백질을 코딩하는 mRNA의 수준은 대조군 세포, 예를 들어 안티센스 올리고머로 처리되지 않은 것 또는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 결합하지 않는 안티센스 올리고머로 처리된 것에서 생성된 SCN1A 단백질을 코딩하는 mRNA의 양과 비교할 때 1.1 내지 10배 감소한다.
일부 실시양태에서, 본 개시 내용의 방법을 사용하여 치료되는 대상체는 하나의 대립 유전자로부터 돌연변이 SCN1A 단백질을 발현하며, 여기서 돌연변이 SCN1A 단백질은 프레임 시프트 돌연변이, 넌센스 돌연변이, 미스센스 돌연변이, 또는 부분 유전자 결실에 의해 야기되고, 돌연변이 SCN1A 단백질은 Nav1.1의 상승한 활성 수준을 야기한다. 일부 실시양태에서, 본 개시 내용의 방법을 사용하여 치료되는 대상체는 프레임 시프트 돌연변이, 넌센스 돌연변이, 미스센스 돌연변이, 또는 부분 유전자 결실로 인해 하나의 대립 유전자로부터 상승한 양의 SCN1A 단백질을 발현한다.
본 발명의 실시양태에서, 대상체는 SCN1A에서 돌연변이를 가질 수 있다. SCN1A에서 돌연변이는 상기 유전자 전체에 퍼져 있을 수 있다. SCN1A 단백질은 4개의 도메인으로 이루어질 수 있다. 상기 SCN1A 도메인은 막 관통 세그먼트를 가질 수 있다. 상기 SCN1A 단백질에서 돌연변이는 상기 단백질 전체에 걸쳐 발생할 수 있다. 상기 SCN1A 단백질은 둘 이상의 아이소형으로 이루어질 수 있다. SCN1A에서 돌연변이는 R931C, R946C, M934I, R1648C, 또는 R1648H를 포함할 수 있다. 일부 경우에는, SCN1A 단백질의 C-말단에서 돌연변이가 관찰될 수 있다. SCN1A 단백질에서 돌연변이는 또한 상기 SCN1A 단백질의 처음 3개 도메인의 세그먼트 5와 6 사이의 루프에서 발견될 수 있다. 일부 경우에, 돌연변이는 SCN1A 단백질의 N-말단에서 관찰될 수 있다. SCN1A 내의 예시적인 돌연변이는 R222X, R712X, I227S, R1892X, W952X, R1245X, R1407X, W1434R, c.4338+1G>A, S1516X, L1670fsX1678, 또는 K1846fsX1856을 포함하지만, 이에 제한되지는 않는다. 본 발명에 의해 표적화될 수 있는 돌연변이는 또한 이온 통로의 세공을 코딩할 수 있다.
일부 실시양태에서, 본원에 기재된 방법 및 조성물은 DS를 치료하는 데 사용될 수 있다. 다른 실시양태에서, 본원에 기재된 방법 및 조성물은 유아기의 중증 근간대성 뇌전증(SMEI)을 치료하는 데 사용될 수 있다. 다른 실시양태에서, 본원에 기재된 방법 및 조성물은 경계성 드라벳 증후군; 열성 발작 플러스를 동반하는 전신 뇌전증 2형; 가족성 열성 발작 3A; 가족성 편마비 편두통 3; 자폐증; 조기 유아 간질성 뇌병증 13; 동기능 부전 증후군　1; 알츠하이머병 또는 SUDEP를 치료하는 데 사용될 수 있다. 본원에 기재된 방법 및 조성물은 또한 경계성 SMEI를 치료하는 데 사용될 수 있다. 또한, 본원에 기재된 방법 및 조성물은 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+)을 치료하는 데 사용될 수 있다. GEFS+는 SCN1B 또는 GABRG2와 같은 뇌전증 관련 이온통로 서브유닛에서의 돌연변이와 관련될 수 있다. 본원에 기재된 방법 및 조성물은 또한 나트륨 이온통로병증을 치료하는 데 사용될 수 있다. 나트륨 이온통로병증은 SCN1A의 돌연변이와 관련될 수 있다. 나트륨 이온통로병증은 또한 베타 서브유닛 SCN1B와 같은 SCN1A의 서브유닛과 관련될 수 있다. 일부 경우에, SCN1A 돌연변이와 관련된 추가 질환이 또한 본 개시 내용으로 치료될 수 있다. SCN1A 돌연변이와 관련된 연관 SCN1A 질환은 선천성 비정형 근긴장증, 고칼슘성 주기성 마비, 및 선천성 이상 근긴장증을 포함하지만 이에 제한되지는 않는다.
일부 실시양태에서, 관련 기술 분야에 공지되어 있고 상기 언급된 문헌(예를 들어 문헌[Hamdan, et al., 2009, Mulley, et al., 2005])에 기재된 임의의 SCN1A 돌연변이를 갖는 대상체는 본원에 기재된 방법 및 조성물을 사용하여 치료될 수 있다. 일부 실시양태에서, 돌연변이는 임의의 SCN1A 인트론 또는 엑손 내에 있다.
엑손 포함
본원에 사용된 바와 같이, "NIE 함유 프리-mRNA"는 하나 이상의 가성 엑손을 함유하는 프리-mRNA 전사체이다. 선택적 또는 비정상적 스플라이싱은 성숙한 mRNA 전사체에 하나 이상의 가성 엑손의 포함을 초래할 수 있다. 용어 "성숙한 mRNA" 및 "완전히 스플라이싱된 mRNA"는 완전히 가공된 mRNA를 기술하기 위해 본원에서 호환적으로 사용된다. 하나 이상의 가성 엑손의 포함으로 비생산적인 mRNA가 될 수 있고 성숙한 mRNA의 NMD를 유발할 수 있다. NIE를 함유하는 성숙한 mRNA는 때때로 비정상적 단백질 발현을 야기할 수 있다.
일부 실시양태에서, 포함된 가성 엑손은 세포에서 표적 단백질을 코딩하는 유전자로부터 전사된 NIE 함유 프리-mRNA 집단에서 가장 풍부한 가성 엑손이다. 일부 실시양태에서, 포함된 가성 엑손은 세포에서 표적 단백질을 코딩하는 유전자로부터 전사된 NIE 함유 프리-mRNA 집단에서 가장 풍부한 가성 엑손이고, 여기서 NIE 함유 프리-mRNA의 집단은 2개 이상의 포함된 가성 엑손을 포함한다. 일부 실시양태에서, 표적 단백질을 코딩하는 NIE 함유 프리-mRNA 집단에서 가장 풍부한 가성 엑손에 표적화되는 안티센스 올리고머는 안티센스 올리고머가 표적화되거나 결합하는 가성 엑손을 포함하여, 집단에서 하나 또는 둘 이상의 가성 엑손의 엑손 스키핑을 유도한다. 실시양태에서, 표적화된 영역은 SCN1A 단백질을 코딩하는 NIE 함유 프리-mRNA에서 가장 풍부한 가성 엑손인 가성 엑손 내에 있다.
엑손 포함의 정도는 퍼센트 엑손 포함, 예를 들어 주어진 가성 엑손이 포함된 전사체의 백분율로 표현될 수 있다. 간략하게, 퍼센트 엑손 포함은 엑손 포함을 갖는 RNA 전사체의 양의 평균 + 엑손 배제를 갖는 RNA 전사체의 양의 평균의 합에 대한 엑손 포함을 갖는 RNA 전사체의 양의 백분율로서 계산될 수 있다.
일부 실시양태에서, 포함된 가성 엑손은 적어도 약 5%, 적어도 약 10%, 적어도 약 15%, 적어도 약 20%, 적어도 약 25%, 적어도 약 30%, 적어도 약 35%, 적어도 약 40%, 적어도 약 45%, 또는 적어도 약 50% 포함의 결정에 기초하여 포함된 가성 엑손으로서 확인된 엑손이다. 일부 실시양태에서, 포함된 가성 엑손은 5% 내지 약 100%, 약 5% 내지 약 95%, 약 5% 내지 약 90%, 약 5% 내지 약 85%, 약 5% 내지 약 80%, 약 5% 내지 약 75%, 약 5% 내지 약 70%, 약 5% 내지 약 65%, 약 5% 내지 약 60%, 약 5% 내지 약 55%, 약 5% 내지 약 50%, 약 5% 내지 약 45%, 약 5% 내지 약 40%, 약 5% 내지 약 35%, 약 5% 내지 약 30%, 약 5% 내지 약 25%, 약 5% 내지 약 20%, 약 5% 내지 약 15%, 약 10% 내지 약 100%, 약 10% 내지 약 95%, 약 10% 내지 약 90%, 약 10% 내지 약 85%, 약 10% 내지 약 80%, 약 10% 내지 약 75%, 약 10% 내지 약 70%, 약 10% 내지 약 65%, 약 10% 내지 약 60%, 약 10% 내지 약 55%, 약 10% 내지 약 50%, 약 10% 내지 약 45%, 약 10% 내지 약 40%, 약 10% 내지 약 35%, 약 10% 내지 약 30%, 약 10% 내지 약 25%, 약 10% 내지 약 20%, 약 15% 내지 약 100%, 약 15% 내지 약 95%, 약 15% 내지 약 90%, 약 15% 내지 약 85%, 약 15% 내지 약 80%, 약 15% 내지 약 75%, 약 15% 내지 약 70%, 약 15% 내지 약 65%, 약 15% 내지 약 60%, 약 15% 내지 약 55%, 약 15% 내지 약 50%, 약 15% 내지 약 45%, 약 15% 내지 약 40%, 약 15% 내지 약 35%, 약 15% 내지 약 30%, 약 15% 내지 약 25%, 약 20% 내지 약 100%, 약 20% 내지 약 95%, 약 20% 내지 약 90%, 약 20% 내지 약 85%, 약 20% 내지 약 80%, 약 20% 내지 약 75%, 약 20% 내지 약 70%, 약 20% 내지 약 65%, 약 20% 내지 약 60%, 약 20% 내지 약 55%, 약 20% 내지 약 50%, 약 20% 내지 약 45%, 약 20% 내지 약 40%, 약 20% 내지 약 35%, 약 20% 내지 약 30%, 약 25% 내지 약 100%, 약 25% 내지 약 95%, 약 25% 내지 약 90%, 약 25% 내지 약 85%, 약 25% 내지 약 80%, 약 25% 내지 약 75%, 약 25% 내지 약 70%, 약 25% 내지 약 65%, 약 25% 내지 약 60%, 약 25% 내지 약 55%, 약 25% 내지 약 50%, 약 25% 내지 약 45%, 약 25% 내지 약 40%, 또는 약 25% 내지 약 35% 포함의 결정에 기초하여 포함된 가성 엑손으로서 확인된 엑손이다. ENCODE 데이터(예를 들어, 문헌[Tilgner, et al., 2012, "Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs," Genome Research 22(9):1616-25]에 기술됨)를 사용하여 엑손 포함을 확인하는데 도움을 줄 수 있다.
일부 실시양태에서, SCN1A 프리-mRNA 전사체의 표적화된 부분에 상보적인 ASO와 세포를 접촉시킴으로써 ASO의 부재/치료의 부재하에 세포에 의해 생성된 SCN1A 단백질의 양과 비교하여 생성된 SCN1A 단백질의 양을 적어도 10, 20, 30, 40, 50, 60, 80, 100, 150, 200, 250, 300, 350, 400, 450, 500, 또는 1000% 증가시킨다. 일부 실시양태에서, 안티센스 올리고머가 접촉되는 세포에 의해 생성된 SCN1A 단백질의 총량은 대조군 화합물에 의해 생성된 표적 단백질의 양과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가한다, 대조군 화합물은 예를 들어 프리-mRNA의 표적화된 부분에 상보적이지 않은 올리고뉴클레오티드일 수 있다.
일부 실시양태에서, SCN1A 프리-mRNA 전사체의 표적화된 부분에 상보적인 ASO와 세포를 접촉시킴으로써 ASO의 부재/치료의 부재하에 세포에 의해 생성된 SCN1A 단백질의 양과 비교하여 생성된 SCN1A 단백질의 양을 적어도 10, 20, 30, 40, 50, 60, 80, 100, 150, 200, 250, 300, 350, 400, 450, 500, 또는 1000% 감소시킨다. 일부 실시양태에서, 안티센스 올리고머가 접촉되는 세포에 의해 생성된 단백질의 총량은 대조군 화합물에 의해 생성된 표적 단백질의 양과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소한다. 대조군 화합물은 예를 들어 프리-mRNA의 표적 부분에 상보적이지 않은 올리고뉴클레오티드일 수 있다.
일부 실시양태에서, SCN1A 프리-mRNA 전사체의 표적화된 부분에 상보적인 ASO와 세포를 접촉시킴으로써 표적 단백질을 코딩하는 성숙한 mRNA를 포함하여 SCN1A를 코딩하는 mRNA의 양을 증가시킨다. 일부 실시양태에서, SCN1A 단백질을 코딩하는 mRNA, 또는 SCN1A 단백질을 코딩하는 성숙한 mRNA의 양은 ASO의 부재/치료의 부재하에 세포에 의해 생성된 단백질의 양과 비교하여 적어도 10, 20, 30, 40, 50, 60, 80, 100, 150, 200, 250, 300, 350, 400, 450, 500, 또는 1000% 증가한다. 일부 실시양태에서, 안티센스 올리고머가 접촉되는 세포에서 생성된 SCN1A 단백질을 코딩하는 mRNA, 또는 SCN1A 단백질을 코딩하는 성숙한 mRNA의 총량은 처리되지 않은 세포, 예를 들어, 처리되지 않은 세포 또는 대조군 화합물로 처리된 세포에서 생성된 성숙한 RNA의 양과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가한다. 대조군 화합물은 예를 들어 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이지 않은 올리고뉴클레오티드일 수 있다.
일부 실시양태에서, SCN1A 프리-mRNA 전사체의 표적화된 부분에 상보적인 ASO와 세포를 접촉시킴으로써 표적 단백질을 코딩하는 성숙한 mRNA를 포함하여 SCN1A를 코딩하는 mRNA의 양을 감소시킨다. 일부 실시양태에서, SCN1A 단백질을 코딩하는 mRNA, 또는 SCN1A 단백질을 코딩하는 성숙한 mRNA의 양은 ASO의 부재/치료의 부재하에 세포에 의해 생성된 단백질의 양과 비교하여 적어도 10, 20, 30, 40, 50, 60, 80, 100, 150, 200, 250, 300, 350, 400, 450, 500, 또는 1000% 감소한다. 일부 실시양태에서, 안티센스 올리고머가 접촉되는 세포에서 생성된 SCN1A 단백질을 코딩하는 mRNA, 또는 SCN1A 단백질을 코딩하는 성숙한 mRNA의 총량은 처리되지 않은 세포, 예를 들어, 처리되지 않은 세포 또는 대조군 화합물로 처리된 세포에서 생성된 성숙한 RNA의 양과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소한다. 대조군 화합물은 예를 들어 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이지 않은 올리고뉴클레오티드일 수 있다.
NIE는 임의의 길이일 수 있다. 일부 실시양태에서, NIE는 인트론의 전체 서열을 포함하고, 이 경우, 이는 인트론 유지로 지칭될 수 있다. 일부 실시양태에서, NIE는 인트론의 일부일 수 있다. 일부 실시양태에서, NIE는 5'ss 서열을 포함하는 인트론의 5' 말단 부분일 수 있다. 일부 실시양태에서, NIE는 3'ss의 서열을 포함하는 인트론의 3' 말단 부분일 수 있다. 일부 실시양태에서, NIE는 5'ss의 서열을 포함하지 않는 인트론 내의 일부일 수 있다. 일부 실시양태에서, NIE는 3'ss의 서열을 포함하지 않는 인트론 내의 일부일 수 있다. 일부 실시 예에서, NIE는 5'ss 또는 3'ss의 서열을 포함하지 않는 인트론 내의 일부일 수 있다. 일부 실시양태에서, NIE는 5 뉴클레오티드 내지 10 뉴클레오티드 길이, 10 뉴클레오티드 내지 15 뉴클레오티드 갈이, 15 뉴클레오티드 내지 20 뉴클레오티드 길이, 20 뉴클레오티드 내지 25 뉴클레오티드 길이, 25 뉴클레오티드 내지 30 뉴클레오티드 길이, 30 뉴클레오티드 내지 35 뉴클레오티드 길이, 35 뉴클레오티드 내지 40 뉴클레오티드 길이, 40 뉴클레오티드 내지 45 뉴클레오티드 길이, 45 뉴클레오티드 내지 50 뉴클레오티드 길이, 50 뉴클레오티드 내지 55 뉴클레오티드 길이, 55 뉴클레오티드 내지 60 뉴클레오티드 길이, 60 뉴클레오티드 내지 65 뉴클레오티드 길이, 65 뉴클레오티드 내지 70 뉴클레오티드 길이, 70 뉴클레오티드 내지 75 뉴클레오티드 길이, 75 뉴클레오티드 내지 80 뉴클레오티드 길이, 80 뉴클레오티드 내지 85 뉴클레오티드 길이, 85 뉴클레오티드 내지 90 뉴클레오티드 길이, 90 뉴클레오티드 내지 95 뉴클레오티드 길이, 또는 95 뉴클레오티드 내지 100 뉴클레오티드 길이일 수 있다. 일부 실시양태에서, NIE는 적어도 10 뉴클레오티드, 적어도 20 뉴클레오티드, 적어도 30 뉴클레오티드, 적어도 40 뉴클레오티드, 적어도 50 뉴클레오티드, 적어도 60 뉴클레오티드, 적어도 70 뉴클레오티드, 적어도 80 뉴클레오티드 길이, 적어도 90 뉴클레오티드, 또는 적어도 100 뉴클레오티드 길이일 수 있다. 일부 실시양태에서, NIE는 100 내지 200 뉴클레오티드 길이, 200 내지 300 뉴클레오티드 길이, 300 내지 400 뉴클레오티드 길이, 400 내지 500 뉴클레오티드 길이, 500 내지 600 뉴클레오티드 길이, 600 내지 700 뉴클레오티드 길이, 700 내지 800 뉴클레오티드 길이, 800 내지 900 뉴클레오티드 길이, 900 내지 1,000 뉴클레오티드 길이일 수 있다. 일부 실시양태에서, NIE는 1,000 뉴클레오티드 길이보다 더 길 수 있다.
가성 엑손의 포함은 프레임 시프트 및 전사체를 NMD의 표적으로 만드는 성숙한 mRNA 전사체에 조기 종결 코돈 (PIC)의 도입을 초래할 수 있다. NIE를 함유하는 성숙한 mRNA 전사체는 단백질 발현을 유발하지 않는 비생산적인 mRNA 전사체일 수 있다. PIC는 NIE의 하류 임의의 위치에 존재할 수 있다. 일부 실시양태에서, PIC는 NIE의 하류의 임의의 엑손에 존재할 수 있다. 일부 실시양태에서, PIC는 NIE 내에 존재할 수 있다. 예를 들어, SCN1A 유전자에 의해 코딩된 mRNA 전사체에 엑손 20x의 포함은 mRNA 전사체에 PIC, 예를 들어 mRNA 전사체의 엑손 21에 PIC가 유도될 수 있다.
치료제
본 개시 내용의 다양한 실시양태에서, SCN1A의 단백질 발현 수준을 조절하기 위해 치료제를 포함하는 조성물 및 방법이 제공된다. 일부 실시양태에서, SCNA1 프리-mRNA의 선택적 스플라이싱을 조절하기 위한 조성물 및 방법이 본원에 제공된다. 일부 실시양태에서, 예를 들어 SCN1A 프리-mRNA의 스플라이싱 중에 가성 엑손의 스키핑을 유도하기 위해, SCN1A 프리-mRNA의 스플라이싱에서 엑손 스키핑을 유도하는 조성물 및 방법이 본원에 제공된다. 다른 실시양태에서, 단백질 발현 수준을 감소시키기 위해 치료제를 사용하여 엑손의 포함을 유도할 수 있다.
일부 실시양태에서, 본원에 개시된 치료제는 소분자, 폴리펩티드, 또는 폴리핵산 중합체이다. 일부 경우에, 치료제는 소분자이다. 일부 경우에, 치료제는 폴리펩티드이다. 일부 경우에, 치료제는 폴리핵산 중합체이다. 일부 경우에, 치료제는 억제제 작용제이다. 추가의 경우에, 치료제는 인핸서 작용제이다.
본원에 개시된 치료제는 NIE 억제제 작용제일 수 있다. 치료제는 폴리핵산 중합체를 포함할 수 있다.
본 개시 내용의 한 측면에 따르면, 기능성 SCN1A 단백질의 수준을 증가시키기 위해 NIE 억제제 작용제를 대상체에게 투여하는 단계를 포함하는 기능성 SCN1A 단백질 결핍과 관련된 병태의 치료 또는 예방 방법으로서, 상기 작용제는 프리-mRNA 전사체의 영역에 결합하여 성숙한 전사체에 NIE의 포함을 감소시키는 것인 방법이 본원에 제공된다. 예를 들어, 기능성 SCN1A 단백질의 수준을 증가시키기 위해 NIE 억제제 작용제를 대상체에게 투여하는 단계를 포함하는 기능성 SCN1A 단백질 결핍과 관련된 병태의 치료 또는 예방 방법으로서, 상기 작용제는 프리-mRNA 전사체의 NIE를 함유하는 인트론의 영역(예를 들어, 인간 SCN1A 유전자에서 인트론 20) 또는 동일한 인트론 내 NIE 활성화 조절 서열에 결합하는 것인 방법이 본원에서 제공된다.
성숙한 mRNA에 NIE 포함을 감소시키는 것이 언급되는 경우, 감소는 완전, 예를 들어 100%일 수 있거나, 부분적일 수 있다. 감소는 임상적으로 유의할 수 있다. 감소/교정은 치료 없는 대상체에서 NIE 포함 수준 또는 유사한 대상체 집단에서 NIE 포함 양에 상대적일 수 있다. 감소/교정은 평균 대상체, 또는 치료 전 대상체에 비해 NIE 포함이 10% 이상 적을 수 있다. 감소는 평균 대상체 또는 치료 전 대상체에 비해 NIE 포함이 20% 이상 적을 수 있다. 감소는 평균 대상체 또는 치료 전 대상체에 비해 NIE 포함이 40% 이상 적을 수 있다. 감소는 평균 대상체 또는 치료 전 대상체에 비해 NIE 포함이 50% 이상 적을 수 있다. 감소는 평균 대상체 또는 치료 전 대상체에 비해 NIE 포함이 60% 이상 적을 수 있다. 감소는 평균 대상체 또는 치료 전 대상체에 비해 NIE 포함이 80% 이상 적을 수 있다. 감소는 평균 대상체 또는 치료 전 대상체에 비해 NIE 포함이 90% 이상 적을 수 있다.
활성 SCN1A 단백질 수준을 증가시키는 것이 언급되는 경우, 증가는 임상적으로 유의할 수 있다. 증가는 치료 없는 대상체에서 활성 SCN1A 단백질의 수준에 상대적일 수 있거나 유사한 대상체 집단에서 활성 SCN1A 단백질의 양에 상대적일 수 있다. 증가는 평균 대상체, 또는 치료 전 대상체에 비해 활성 SCN1A 단백질이 10% 이상 많을 수 있다. 증가는 평균 대상체, 또는 치료 전 대상체에 비해 20% 이상 많을 수 있다. 증가는 평균 대상체, 또는 치료 전 대상체에 비해 활성 SCN1A 단백질이 40% 이상 많을 수 있다. 증가는 평균 대상체, 또는 치료 전 대상체에 비해 활성 SCN1A 단백질이 50% 이상 많을 수 있다. 증가는 평균 대상체, 또는 치료 전 대상체에 비해 활성 SCN1A 단백질이 80% 이상 많을 수 있다. 증가는 평균 대상체, 또는 치료 전 대상체에 비해 활성 SCN1A 단백질이 100% 이상 많을 수 있다. 증가는 평균 대상체, 또는 치료 전 대상체에 비해 활성 SCN1A 단백질이 200% 이상 많을 수 있다. 증가는 평균 대상체, 또는 치료 전 대상체에 비해 활성 SCN1A 단백질이 500% 이상 많을 수 있다.
NIE 억제제 작용제가 폴리핵산 중합체를 포함하는 실시양태에서, 폴리핵산 중합체는 약 50 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 45 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 40 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 35 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 30 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 24 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 25 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 20 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 19 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 18 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 17 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 16 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 15 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 14 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 13 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 12 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 11 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 10 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 10 내지 약 50 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 10 내지 약 45 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 10 내지 약 40 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 10 내지 약 35 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 10 내지 약 30 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 10 내지 약 25 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 10 내지 약 20 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 15 내지 약 25 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 15 내지 약 30 뉴클레오티드 길이일 수 있다. 폴리핵산 중합체는 약 12 내지 약 30 뉴클레오티드 길이일 수 있다.
폴리핵산 중합체의 서열은 mRNA 전사체, 예를 들어 부분적으로 가공된 mRNA 전사체의 표적 서열과 적어도 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 99.5% 상보적일 수 있다. 폴리핵산 중합체의 서열은 프리-mRNA 전사체의 표적 서열에 100% 상보적일 수 있다.
폴리핵산 중합체의 서열은 프리-mRNA 전사체의 표적 서열과 4개 이하의 불일치를 가질 수 있다. 폴리핵산 중합체의 서열은 프리-mRNA 전사체의 표적 서열과 3개 이하의 불일치를 가질 수 있다. 폴리핵산 중합체의 서열은 프리-mRNA 전사체의 표적 서열과 2개 이하의 불일치를 가질 수 있다. 폴리핵산 중합체의 서열은 프리-mRNA 전사체의 표적 서열과 1개 이하의 불일치를 가질 수 있다. 폴리핵산 중합체의 서열은 프리-mRNA 전사체의 표적 서열과 불일치를 갖지 않을 수 있다.
폴리핵산 중합체는 프리-mRNA 전사체의 표적 서열에 특이적으로 혼성화할 수 있다. 예를 들어, 폴리핵산 중합체는 프리-mRNA 전사체의 표적 서열에 대해 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% 또는 100% 서열 상보성을 가질 수 있다. 혼성화는 매우 엄격한 혼성화 조건하에 있을 수 있다.
폴리핵산 중합체는 서열 번호 21 내지 67로 이루어진 군으로부터 선택된 서열과 적어도 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 99.5% 서열 동일성을 갖는 서열을 가질 수 있다. 폴리핵산 중합체는 서열 번호 21 내지 67로 이루어진 군으로부터 선택된 서열과 100% 서열 동일성을 갖는 서열을 가질 수 있다. 일부 경우에, 폴리핵산 중합체는 서열 번호 68 내지 114로 이루어진 군으로부터 선택된 서열과 적어도 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 또는 99.5% 서열 동일성을 갖는 서열을 가질 수 있다. 일부 경우에, 폴리핵산 중합체는 서열 번호 68 내지 114로 이루어진 군으로부터 선택된 서열과 100% 서열 동일성을 갖는 서열을 가질 수 있다.
폴리핵산 중합체 서열이 언급되는 경우, 당업자는 표적 서열에 혼성화하는 능력; 또는 표적 서열에 치환이 있는 경우, 표적 서열로 인식될 수 있는 능력이 유지되기 위해서 서열에서 하나 이상의 치환이 허용될 수 있고, 경우에 따라 2개의 치환이 허용될 수 있음을 이해할 것이다. 서열 동일성에 대한 기준은 표준/기본 파라미터를 사용한 BLAST 서열 정렬에 의해 결정될 수 있다. 예를 들어, 서열은 99% 동일성을 갖고 본 개시에 따라 여전히 기능을 할 수 있다. 다른 실시양태에서, 서열은 98% 동일성을 가질 수 있고 본 개시 내용에 따라 여전히 기능을 할 수 있다. 다른 실시 형태에서, 서열은 95% 동일성을 가질 수 있고 본 발명에 따라 여전히 기능을 할 수 있다. 다른 실시양태에서, 서열은 90% 동일성을 갖고 본 개시 내용에 따라 여전히 기능을 할 수 있다.
안티센스 올리고머
SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 결합함으로써 엑손 스키핑을 유도하는 안티센스 올리고머를 포함하는 조성물이 본원에 제공된다. 본원에 사용된 바와 같이, 용어 "ASO" 및 "안티센스 올리고머"는 호환적으로 사용되며, 왓슨-크릭(Watson-Crick) 염기 짝짓기 또는 워블(wobble) 염기 짝짓기(G-U)에 의해 표적 핵산(예를 들어, SCN1A NIE 함유 프리-mRNA) 서열에 혼성화하는 핵염기를 포함하는 폴리뉴클레오티드와 같은 올리고머를 지칭한다. ASO는 표적 서열에 상보적이거나 또는 상보성에 가까운(예를 들어, 표적 서열에 결합하고 스플라이스 부위에서 스플라이싱을 향상시키기에 충분한 상보성) 정확한 서열을 가질 수 있다. ASO는 이들이 표적 핵산(예를 들어, 프리-mRNA 전사체의 표적화된 부분)에 결합(혼성화)하고 생리 학적 조건하에서 혼성화된 상태를 유지하도록 설계된다. 전형적으로, 이들이 의도된(표적된) 핵산 서열 이외의 부위에 혼성화하는 경우, 이들은 표적 핵산이 아닌 제한된 수의 서열에(표적 핵산 이외의 몇몇 부위에) 혼성화된다. ASO가 다른 부위에 결합하고 "표적 외(off-target)" 효과를 야기할 가능성을 제한되도록 ASO의 설계는 프리-mRNA 전사체의 표적화된 부분의 핵산 서열의 발생 또는 게놈 또는 세포 프리-mRNA 또는 전사체의 다른 위치에서 충분히 유사한 핵산 서열의 발생을 고려할 수 있다. 당 업계에 알려진, 예를 들어 WO 2015/035091호로 공개된 PCT 출원 PCT/US2014/054151호(발명의 명칭 "Reducing Nonsense-Mediated mRNA Decay", 본원에서 참고로 포함됨)에서의 임의의 안티센스 올리고머는 본원에 기재된 방법을 실시하는 데 사용될 수 있다.
일부 실시양태에서, ASO는 표적 핵산 또는 NIE 함유 프리-mRNA의 표적화된 부분에 "특이적으로 혼성화"하거나 "특이적"이다. 전형적으로 이러한 혼성화는 실질적으로 37℃ 초과, 바람직하게는 50℃ 이상, 전형적으로 60℃ 내지 대략 90℃의 Tm에서 발생한다. 이러한 혼성화는 바람직하게는 엄격한 혼성화 조건에 해당한다. 주어진 이온 강도 및 pH에서, Tm은 표적 서열의 50%가 상보적인 올리고뉴클레오티드에 혼성화하는 온도이다.
올리고뉴클레오티드와 같은 올리고머는 2개의 단일 가닥 폴리뉴클레오티드 사이의 역평행 배열로 혼성화가 일어날 때 서로 "상보적"이다. 이중 가닥 폴리뉴클레오티드는 제1 폴리뉴클레오티드의 가닥 중 하나와 제2 폴리뉴클레오티드 사이에서 혼성화가 발생할 수 있는 경우 다른 폴리뉴클레오티드에 대해 "상보적"일 수 있다. 상보성(하나의 폴리뉴클레오티드가 다른 폴리뉴클레오티드와 상보적인 정도)은 일반적으로 허용되는 염기 짝짓기 규칙에 따라 서로 수소 결합을 형성할 것으로 예상되는 반대 가닥의 염기의 비율(예를 들어, 백분율)에 대해 정량화할 수 있다. 안티센스 올리고머(ASO)의 서열은 혼성화하기 위해 그의 표적 핵산의 서열과 100% 상보적일 필요는 없다. 특정 실시양태에서, ASO는 그들이 표적화되는 표적 핵산 서열 내의 표적 영역과 적어도 70%, 적어도 75%, 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 96%, 적어도 97%, 적어도 98%, 또는 적어도 99% 서열 상보성을 포함할 수 있다. 예를 들어, 올리고머 화합물의 20개 핵염기 중 18개가 표적 영역에 상보적이고, 따라서 특이적으로 혼성화하는 ASO는 90% 상보성을 나타낸다. 이 예에서, 나머지 비-상보적인 핵염기는 함께 클러스터링되거나 상보적인 핵염기와 함께 산재될 수 있으며 서로 또는 상보적인 핵염기에 대해 인접할 필요는 없다. 표적 핵산의 영역과 ASO의 상보성 백분율은 당 업계에 공지된 BLAST 프로그램(기본 국소 정렬 검색 도구) 및 PowerBLAST 프로그램(Altschul, et al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656)을 사용하여 통상적으로 결정될 수 있다.
ASO는 표적 서열에서 모든 핵염기에 혼성화할 필요는 없고, 그가 혼성화하는 핵염기는 인접하거나 비인접할 수 있다. ASO는 프리-mRNA 전사체의 하나 이상의 세그먼트에 걸쳐 혼성화할 수 있어서, 개재 또는 인접 세그먼트가 혼성화 이벤트에 관여하지 않는다(예를 들어, 루프 구조 또는 헤어핀 구조가 형성될 수 있음). 특정 실시양태에서, ASO는 표적 프리-mRNA 전사체에서 비인접한 핵염기에 혼성화한다. 예를 들어, ASO는 ASO가 혼성화하지 않는 하나 이상의 핵염기(들)에 의해 분리된 프리-mRNA 전사체에서 핵염기에 혼성화할 수 있다.
본원에 기재된 ASO는 NIE 함유 프리-mRNA의 표적화된 부분에 존재하는 핵염기에 상보적인 핵염기를 포함한다. 용어 ASO는 올리고뉴클레오티드 및 표적 mRNA 상의 상보적 핵염기와 혼성화할 수 있는 핵염기는 포함하지만 펩티드 핵산(PNA)과 같은 당 모이어티를 포함하지 않는 임의의 다른 올리고머 분자를 포함한다. ASO는 자연 발생 뉴클레오티드, 뉴클레오티드 유사체, 변형된 뉴클레오티드, 또는 상기한 것 중 둘 또는 셋의 임의의 조합을 포함할 수 있다. 용어 "자연 발생 뉴클레오티드"는 데옥시리보뉴클레오티드 및 리보뉴클레오티드를 포함한다. 용어 "변형된 뉴클레오티드"는 변형되거나 치환된 당 기를 갖고/하거나 변형된 백본을 갖는 뉴클레오티드를 포함한다. 일부 실시양태에서, ASO의 모든 뉴클레오티드는 변형된 뉴클레오티드이다. 본원에 기재된 방법 및 조성물과 상용성인 ASO 또는 ASO의 성분의 화학적 변형은 당업자에게 명백할 것이며, 예를 들어 미국 특허 제8,258,109 B2호, 미국 특허 제5,656,612호, 미국 특허 공개 제2012/0190728호, 및 문헌[and Dias and Stein, Mol. Cancer Ther. 2002, 347-355]에서 찾아볼 수 있으며, 이들은 그 전문이 본원에 참고로 포함된다.
ASO의 하나 이상의 핵염기는 임의의 자연 발생, 변형되지 않은 핵염기, 예를 들어 아데닌, 구아닌, 시토신, 티민 및 우라실, 또는 변형되지 않은 핵염기와 충분히 유사하여 그것이 표적 프리-mRNA 상에 존재하는 핵염기와 수소 결합할 수 있는 임의의 합성 또는 변형된 핵염기일 수 있다. 변형된 핵염기의 예로는 히포크산틴, 크산틴, 7-메틸구아닌, 5,6-디히드로우라실, 5-메틸시토신, 및 5-히드록시메토일 시토신이 제한 없이 포함된다.
본원에 기재된 ASO는 또한 올리고머의 성분을 연결하는 백본 구조를 포함한다. 용어 "백본 구조" 및 "올리고머 결합"은 호환적으로 사용될 수 있으며 ASO의 단량체 사이의 연결을 지칭한다. 자연 발생 올리고뉴클레오티드에서, 백본은 올리고머의 당 모이어티를 연결하는 3'-5' 포스포디에스테르 결합을 포함한다. 본원에 기재된 ASO의 백본 구조 또는 올리고머 결합은 포스포로티오에이트, 포스포로디티오에이트, 포스포로셀레노에이트, 포스포로디셀레노에이트, 포스포로아닐로티오에이트, 포스포라닐라데이트, 포스포라미데이트 등을 포함할 수 있다(그러나, 이에 이에 제한되지는 않음). 예를 들어, 문헌[LaPlanche, et al., Nucleic Acids Res. 14:9081 (1986); Stec, et al., J. Am. Chem. Soc. 106:6077 (1984), Stein, et al., Nucleic Acids Res. 16:3209 (1988), Zon, et al., Anti-Cancer Drug Design 6:539 (1991); Zon, et al., Oligonucleotides and Analogues: A Practical Approach, pp. 87-108 (F. Eckstein, Ed., Oxford University Press, Oxford England (1991)); Stec, et al., 미국 특허 제5,151,510호; Uhlmann and Peyman, Chemical Reviews 90:543 (1990)]을 참조한다. 일부 실시양태에서, ASO의 백본 구조는 인을 함유하지 않고, 오히려 예를 들어 펩티드 핵산(PNA) 내, 펩티드 결합, 또는 카바메이트, 아미드, 및 선형 및 환식 탄화수소 기를 포함하는 연결 기를 함유한다. 일부 실시양태에서, 백본 변형은 포스포티오에이트 결합이다. 일부 실시양태에서, 백본 변형은 포스포라미데이트 결합이다.
실시양태에서, ASO 백본의 인 뉴클레오티드 간 결합의 각각에서 입체 화학은 무작위적이다. 실시양태에서, ASO 백본의 인 뉴클레오티드 간 결합의 각각에서 입체 화학은 제어되고 무작위적이지 않다. 예를 들어, 본원에 참고로 포함된 미국 특허 출원 제2014/0194610호("Methods for the Synthesis of Functionalized Nucleic Acids,")는 핵산 올리고머에서 각각의 인 원자에서 키랄 선성(handedness of chirality)을 독립적으로 선택하는 방법을 기술한다. 실시양태에서, 표 5 및 6에 본원에 제시된 임의의 ASO를 포함하는, 그러나 이에 제한되지 않는 본 발명의 방법에 사용된 ASO는 무작위적이지 않은 인 뉴클레오티드 간 결합을 갖는 ASO를 포함한다. 실시양태에서, 본 발명의 방법에 사용된 조성물은 순수한 부분 입체 이성질체 ASO를 포함한다. 실시양태에서, 본 발명의 방법에 사용된 조성물은 약 90% 이상, 약 91% 이상, 약 92% 이상, 약 93% 이상, 약 94% 이상, 약 95% 이상, 약 96% 이상, 약 97% 이상, 약 98% 이상, 약 99% 이상, 약 100%, 약 90% 내지 약 100%, 약 91% 내지 약 100%, 약 92% 내지 약 100%, 약 93% 내지 약 100%, 약 94% 내지 약 100%, 약 95% 내지 약 100%, 약 96% 내지 약 100%, 약 97% 내지 약 100%, 약 98% 내지 약 100%, 또는 약 99% 내지 약 100%의 부분 입체 이성질체 순도를 갖는 ASO를 포함한다.
실시양태에서, ASO는 그의 인 뉴클레오티드 간 결합에서 Rp 및 Sp 배열의 비무작위 혼합물을 갖는다. 예를 들어, 우수한 활성과 뉴클레아제 안정성 사이의 균형을 달성하기 위해 안티센스 올리고뉴클레오티드에서 Rp 및 Sp의 혼합이 필요하다는 것이 제안되었다(Wan, et al., 2014, "Synthesis, biophysical properties and biological activity of second generation antisense oligonucleotides containing chiral phosphorothioate linkages," Nucleic Acids Research 42(22): 13456-13468, 본원에 참고로 포함됨). 실시양태에서, 서열 번호 21 내지 114에 본원에 제시된 임의의 ASO를 포함하는, 그러나 이에 제한되지 않는 본 발명의 방법에 사용되는 ASO는 약 5 내지 100% Rp, 적어도 약 5% Rp, 적어도 약 10% Rp, 적어도 약 15% Rp, 적어도 약 20% Rp, 적어도 약 25% Rp, 적어도 약 30% Rp, 적어도 약 35% Rp, 적어도 약 40% Rp, 적어도 약 45% Rp, 적어도 약 50% Rp, 적어도 약 55% Rp, 적어도 약 60% Rp, 적어도 약 65% Rp, 적어도 약 70% Rp, 적어도 약 75% Rp, 적어도 약 80% Rp, 적어도 약 85% Rp, 적어도 약 90% Rp, 또는 적어도 약 95% Rp, 그리고 나머지의 Sp, 또는 약 100% Rp를 포함한다. 실시양태에서, 서열 21 내지 114에 본원에 기재된 임의의 ASO를 포함하는, 그러나 이에 제한되지 않는 본 발명의 방법에 사용되는 ASO는 약 10% 내지 약 100% Rp, 약 15% 내지 약 100% Rp, 약 20% 내지 약 100% Rp, 약 25% 내지 약 100% Rp, 약 30% 내지 약 100% Rp, 약 35% 내지 약 100% Rp, 약 40% 내지 약 100% Rp, 약 45% 내지 약 100% Rp, 약 50% 내지 약 100% Rp, 약 55% 내지 약 100% Rp, 약 60% 내지 약 100% Rp, 약 65% 내지 약 100% Rp, 약 70% 내지 약 100% Rp, 약 75% 내지 약 100% Rp, 약 80% 내지 약 100% Rp, 약 85% 내지 약 100% Rp, 약 90% 내지 약 100% Rp, 또는 약 95% 내지 약 100% Rp, 약 20% 내지 약 80% Rp, 약 25% 내지 약 75% Rp, 약 30% 내지 약 70% Rp, 약 40% 내지 약 60% Rp, 또는 약 45% 내지 약 55% Rp, 그리고 나머지의 Sp를 포함한다.
실시양태에서, 서열 21 내지 114에 본원에 기재된 임의의 ASO를 포함하는, 그러나 이에 제한되지 않는 본 발명의 방법에 사용되는 ASO는 약 5 내지 100% Sp, 적어도 약 5% Sp, 적어도 약 10% Sp, 적어도 약 15% Sp, 적어도 약 20% Sp, 적어도 약 25% Sp, 적어도 약 30% Sp, 적어도 약 35% Sp, 적어도 약 40% Sp, 적어도 약 45% Sp, 적어도 약 50% Sp, 적어도 약 55% Sp, 적어도 약 60% Sp, 적어도 약 65% Sp, 적어도 약 70% Sp, 적어도 약 75% Sp, 적어도 약 80% Sp, 적어도 약 85% Sp, 적어도 약 90% Sp, 또는 적어도 약 95% Sp, 그리고 나머지의 Rp, 또는 약 100% Sp를 포함한다. 실시양태에서, 서열 21 내지 114에 본원에 기재된 임의의 ASO를 포함하는, 그러나 이에 제한되지 않는 본 발명의 방법에 사용되는 ASO는 약 10% 내지 약 100% Sp, 약 15% 내지 약 100% Sp, 약 20% 내지 약 100% Sp, 약 25% 내지 약 100% Sp, 약 30% 내지 약 100% Sp, 약 35% 내지 약 100% Sp, 약 40% 내지 약 100% Sp, 약 45% 내지 약 100% Sp, 약 50% 내지 약 100% Sp, 약 55% 내지 약 100% Sp, 약 60% 내지 약 100% Sp, 약 65% 내지 약 100% Sp, 약 70% 내지 약 100% Sp, 약 75% 내지 약 100% Sp, 약 80% 내지 약 100% Sp, 약 85% 내지 약 100% Sp, 약 90% 내지 약 100% Sp, 또는 약 95% 내지 약 100% Sp, 약 20% 내지 약 80% Sp, 약 25% 내지 약 75% Sp, 약 30% 내지 약 70% Sp, 약 40% 내지 약 60% Sp, 또는 약 45% 내지 약 55% Sp, 그리고 나머지의 Rp를 포함한다.
본원에 기재된 임의의 ASO는 자연 발생 뉴클레오티드에 존재하는 리보오스 또는 데옥시리보오스, 또는 변형된 당 모이어티, 또는 모르폴린 고리를 포함하는 당 유사체를 포함하는 당 모이어티를 함유할 수 있다. 변형된 당 모이어티의 비제한적 예는 2' 치환, 예를 들어 2'-O-메틸(2'-O-Me), 2'-O-메톡시에틸(2'MOE), 2'-O-아미노에틸, 2'F; N3'->P5' 포스포라미데이트, 2'디메틸아미노옥시에톡시, 2'디메틸아미노에톡시에톡시, 2'-구아니디니듐, 2'-O-구아니디늄 에틸, 카바메이트 변형된 당, 및 이환식 변형된 당을 포함한다. 일부 실시양태에서, 당 모이어티 변형은 2'-O-Me, 2'F, 및 2'MOE로부터 선택된다. 일부 실시양태에서, 당 모이어티 변형은 잠금 핵산(LNA)에서와 같은 추가의 가교 결합이다. 일부 실시양태에서, 당 유사체는 포스포로디아미데이트 모르폴리노(PMO)와 같은 모르폴린 고리를 함유한다. 일부 실시양태에서, 당 모이어티는 리보푸란실 또는 2'데옥시리보푸란실 변형을 포함한다. 일부 실시양태에서, 당 모이어티는 2'4'-구속된 2'O-메틸옥시에틸(cMOE) 변형을 포함한다. 일부 실시양태에서, 당 모이어티는 cEt 2', 4' 구속된 2'-O 에틸 BNA 변형을 포함한다. 일부 실시양태에서, 당 모이어티는 트리시클로 DNA(tcDNA) 변형을 포함한다. 일부 실시양태에서, 당 모이어티는 에틸렌 핵산(ENA) 변형을 포함한다. 일부 실시양태에서, 당 모이어티는 MCE 변형을 포함한다. 변형은 당 업계에 공지되어 있고 문헌, 예를 들어 본원에서 이러한 목적을 위해 참고로 포함된 문헌[Jarver, et al., 2014, "A Chemical View of Oligonucleotides for Exon Skipping and Related Drug Applications," Nucleic Acid Therapeutics 24(1): 37-47]에 기술되어 있다.
일부 실시양태에서, ASO의 각 단량체는 동일한 방식으로 변형되며, 예를 들어 ASO의 백본의 각각의 결합은 포스포로티오에이트 결합을 포함하거나 각각의 리보오스 당 모이어티는 2'O-메틸 변형을 포함한다. ASO의 각 단량체 성분에 존재하는 이러한 변형은 "균일한 변형"으로 지칭된다. 일부 예에서, 상이한 변형의 조합이 바람직할 수 있으며, 예를 들어, ASO는 포스포로디아미데이트 결합과 모르폴린 고리(모르폴리노)를 포함하는 당 모이어티의 조합을 포함할 수 있다. ASO에 대한 상이한 변형의 조합은 "혼합 변형" 또는 "혼합 화학"으로 지칭된다.
일부 실시양태에서, ASO는 하나 이상의 백본 변형을 포함한다. 일부 실시양태에서, ASO는 하나 이상의 당 모이어티 변형을 포함한다. 일부 실시양태에서, ASO는 하나 이상의 백본 변형 및 하나 이상의 당 모이어티 변형을 포함한다. 일부 실시양태에서, ASO는 2'MOE 변형 및 포스포로티오에이트 백본을 포함한다. 일부 실시양태에서, ASO는 포스포로디아미데이트 모르폴리노(PMO)를 포함한다. 일부 실시양태에서, ASO는 펩티드 핵산(PNA)을 포함한다. 본원에 기재된 임의의 ASO 또는 ASO의 임의의 성분(예를 들어, 핵염기, 당 모이어티, 백본)은 ASO의 원하는 특성 또는 활성을 달성하거나 ASO의 원하지 않는 특성 또는 활성을 감소시키기 위해 변형될 수 있다. 예를 들어, ASO 또는 임의의 ASO의 하나 이상의 성분은 변형되어 프리-mRNA 전사체 상의 표적 서열에 대한 결합 친화성을 향상시키고/거나; 임의의 비-표적 서열에 대한 결합을 감소시키고/거나; 세포 뉴클레아제(즉, RNase H)에 의한 분해를 감소시키고/거나; 세포 및/또는 세포의 핵으로의 ASO의 흡수를 개선시키고/거나; ASO의 약동학 또는 약력학을 변경하고/거나; ASO의 반감기를 조절할 수 있다.
일부 실시양태에서, ASO는 2'-O-(2-메톡시에틸)(MOE) 포스포로티오에이트-변형된 뉴클레오티드로 구성된다. 이러한 뉴클레오티드로 구성된 ASO는 본원에 개시된 방법에 특히 적합하며; 이러한 변형을 갖는 올리고머는 뉴클레아제 분해에 대한 내성이 상당히 향상되고, 생체 이용률이 증가하여, 예를 들어 본원에 기재된 일부 실시양태에서 경구 전달에 적합하게 만드는 것으로 나타났다. 예를 들어, 문헌[Geary, et al., J Pharmacol Exp Ther. 2001; 296(3):890-7; Geary, et al., J Pharmacol Exp Ther. 2001; 296(3):898-904] 참조.
ASO를 합성하는 방법은 당업자에게 공지될 것이다. 대안적으로 또는 추가로, ASO는 상업적 공급원으로부터 얻을 수 있다.
달리 명시되지 않는 한, 단일 가닥 핵산(예를 들어, 프리-mRNA 전사체, 올리고뉴클레오티드, ASO 등) 서열의 좌측 말단은 5' 말단이고 단일 또는 이중 가닥 핵산 서열의 좌측 방향은 5' 방향으로 지칭된다. 유사하게, 핵산 서열(단일 또는 이중 가닥)의 우측 말단 또는 방향은 3' 말단 또는 방향이다. 일반적으로, 핵산에서 기준점에 대해 5'인 영역 또는 서열을 "상류"로 지칭하고, 핵산에서 기준점에 대해 3'인 영역 또는 서열을 "하류"로 지칭한다. 일반적으로 mRNA의 5' 방향 또는 말단은 개시 또는 시작 코돈이 위치하는 곳인 반면, 3' 말단 또는 방향은 종결 코돈이 위치하는 곳이다. 일부 측면에서, 핵산에서 기준점의 상류에 있는 뉴클레오티드는 음수로 지정될 수 있는 반면, 기준점의 하류에 있는 뉴클레오티드는 양수로 지정될 수 있다. 예를 들어, 기준점(예를 들어, mRNA에서의 엑손-엑손 접합부)은 "0(zero)" 부위로 지정될 수 있고, 기준점의 바로 인접하고 상류에 있는 뉴클레오티드는 "마이너스 1", 예를 들어 "-1"로 지정되는 반면, 기준점의 바로 인접하고 하류에 있는 뉴클레오티드는 "플러스 1", 예를 들어 "+1"로 지정된다.
일부 실시양태에서, ASO는 SCN1A NIE 함유 프리-mRNA에 포함된 엑손의 5' 스플라이스 부위(또는 NIE의 3' 말단)의 하류(3' 방향)(예를 들어, 5' 스플라이스 부위에 대해 양수로 지정되는 방향)에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이다(결합한다). 일부 실시양태에서, ASO는 포함된 엑손의 5' 스플라이스 부위(또는 3'말단)에 대해 약 +1 내지 약 +500의 영역 내에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이다. 일부 실시양태에서, ASO는 포함된 엑손의 5' 스플라이스 부위(또는 3' 말단)에 대해 뉴클레오티드 +6 내지 +496의 영역 내에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적일 수 있다. 일부 측면에서, ASO는 포함된 엑손의 5' 스플라이스 부위(또는 3' 말단)에 대해 약 +1 내지 약 +500, 약 +1 내지 약 +490, 약 +1 내지 약 +480, 약 +1 내지 약 +470, 약 +1 내지 약 +460, 약 +1 내지 약 +450, 약 +1 내지 약 +440, 약 +1 내지 약 +430, 약 +1 내지 약 +420, 약 +1 내지 약 +410, 약 +1 내지 약 +400, 약 +1 내지 약 +390, 약 +1 내지 약 +380, 약 +1 내지 약 +370, 약 +1 내지 약 +360, 약 +1 내지 약 +350, 약 +1 내지 약 +340, 약 +1 내지 약 +330, 약 +1 내지 약 +320, 약 +1 내지 약 +310, 약 +1 내지 약 +300, 약 +1 내지 약 +290, 약 +1 내지 약 +280, 약 +1 내지 약 +270, 약 +1 내지 약 +260, 약 +1 내지 약 +250, 약 +1 내지 약 +240, 약 +1 내지 약 +230, 약 +1 내지 약 +220, 약 +1 내지 약 +210, 약 +1 내지 약 +200, 약 +1 내지 약 +190, 약 +1 내지 약 +180, 약 +1 내지 약 +170, 약 +1 내지 약 +160, 약 +1 내지 약 +150, 약 +1 내지 약 +140, 약 +1 내지 약 +130, 약 +1 내지 약 +120, 약 +1 내지 약 +110, 약 +1 내지 약 +100, 약 +1 내지 약 +90, 약 +1 내지 약 +80, 약 +1 내지 약 +70, 약 +1 내지 약 +60, 약 +1 내지 약 +50, 약 +1 내지 약 +40, 약 +1 내지 약 +30, 또는 약 +1 내지 약 +20의 영역 내에 있는 표적화된 부분에 상보적이다. 일부 측면에서, ASO는 포함된 엑손의 5' 스플라이스 부위(또는 3' 말단)에 대해 약 +1 내지 약 +100, 약 +100 내지 약 +200, 약 +200 내지 약 +300, 약 +300 내지 약 +400, 또는 약 +400 내지 약 +500의 영역 내에 있는 표적화된 부분에 상보적이다.
일부 실시양태에서, ASO는 SCN1A NIE 함유 프리-mRNA에 포함된 엑손의 5' 스플라이스 부위(또는 3' 말단)의 상류(5' 방향)(예를 들어, 5' 스플라이스 부위에 대해 음수로 지정되는 방향)에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이다(결합한다). 일부 실시양태에서, ASO는 포함된 엑손의 5' 스플라이스 부위(또는 3' 말단)에 대해 약 -4 내지 약 -270의 영역 내에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이다. 일부 실시양태에서, ASO는 포함된 엑손의 5' 스플라이스 부위(또는 3' 말단)에 대해 뉴클레오티드 -1 내지 -264의 영역 내에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적일 수 있다. 일부 측면에서, ASO는 포함된 엑손의 5' 스플라이스 부위(또는 3' 말단)에 대해 약 -1 내지 약 -270, 약 -1 내지 약 -260, 약 -1 내지 약 -250, 약 -1 내지 약 -240, 약 -1 내지 약 -230, 약 -1 내지 약 -220, 약 -1 내지 약 -210, 약 -1 내지 약 -200, 약 -1 내지 약 -190, 약 -1 내지 약 -180, 약 -1 내지 약 -170, 약 -1 내지 약 -160, 약 -1 내지 약 -150, 약 -1 내지 약 -140, 약 -1 내지 약 -130, 약 -1 내지 약 -120, 약 -1 내지 약 -110, 약 -1 내지 약 -100, 약 -1 내지 약 -90, 약 -1 내지 약 -80, 약 -1 내지 약 -70, 약 -1 내지 약 -60, 약 -1 내지 약 -50, 약 -1 내지 약 -40, 약 -1 내지 약 -30, 또는 약 -1 내지 약 -20의 영역 내에 있는 표적화된 부분에 상보적이다. 일부 측면에서, ASO는 포함된 엑손의 5' 스플라이스 부위(또는 3' 말단)에 대해 약 -1 내지 약 -50, 약 -50 내지 약 -100, 약 -100 내지 약 -150, 약 -150 내지 약 -200, 또는 약 -200 내지 약 -250의 영역 내에 있는 표적화된 부분에 상보적이다.
일부 실시양태에서, ASO는 SCN1A NIE 함유 프리-mRNA에 포함된 엑손의 3' 스플라이스 부위(또는 5' 말단)의 상류(5' 방향)(예를 들어, 음수로 지정되는 방향)에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이다. 일부 실시양태에서, ASO는 포함된 엑손의 3' 스플라이스 부위(또는 5' 말단)에 대해 약 -1 내지 약 -500의 영역 내에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이다. 일부 실시양태에서, ASO는 포함된 엑손의 3' 스플라이스 부위에 대해 -1 내지 -496의 영역 내에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이다. 일부 측면에서, ASO는 포함된 엑손의 3' 스플라이스 부위에 대해 약 -1 내지 약 -500, 약 -1 내지 약 -490, 약 -1 내지 약 -480, 약 -1 내지 약 -470, 약 -1 내지 약 -460, 약 -1 내지 약 -450, 약 -1 내지 약 -440, 약 -1 내지 약 -430, 약 -1 내지 약 -420, 약 -1 내지 약 -410, 약 -1 내지 약 -400, 약 -1 내지 약 -390, 약 -1 내지 약 -380, 약 -1 내지 약 -370, 약 -1 내지 약 -360, 약 -1 내지 약 -350, 약 -1 내지 약 -340, 약 -1 내지 약 -330, 약 -1 내지 약 -320, 약 -1 내지 약 -310, 약 -1 내지 약 -300, 약 -1 내지 약 -290, 약 -1 내지 약 -280, 약 -1 내지 약 -270, 약 -1 내지 약 -260, 약 -1 내지 약 -250, 약 -1 내지 약 -240, 약 -1 내지 약 -230, 약 -1 내지 약 -220, 약 -1 내지 약 -210, 약 -1 내지 약 -200, 약 -1 내지 약 -190, 약 -1 내지 약 -180, 약 -1 내지 약 -170, 약 -1 내지 약 -160, 약 -1 내지 약 -150, 약 -1 내지 약 -140, 약 -1 내지 약 -130, 약 -1 내지 약 -120, 약 -1 내지 약 -110, 약 -1 내지 약 -100, 약 -1 내지 약 -90, 약 -1 내지 약 -80, 약 -1 내지 약 -70, 약 -1 내지 약 -60, 약 -1 내지 약 -50, 약 -1 내지 약 -40, 또는 약 -1 내지 약 -30의 영역 내에 있는 표적화된 부분에 상보적이다. 일부 측면에서, ASO는 포함된 엑손의 3' 스플라이스 부위에 대해 약 -1 내지 약 -100, 약 -100 내지 약 -200, 약 -200 내지 약 -300, 약 -300 내지 약 -400, 또는 약 -400 내지 약 -500의 영역 내에 있는 표적화된 부분에 상보적이다.
일부 실시양태에서, ASO는 SCN1A NIE 함유 프리-mRNA에 포함된 엑손의 3' 스플라이스 부위(또는 5' 말단)의 하류(3' 방향)(예를 들어, 양수로 지정되는 방향)에 있는 i NIE 함유 프리-mRNA의 표적화된 부분에 상보적이다. 일부 실시양태에서, ASO는 포함된 엑손의 3' 스플라이스 부위에 대해 약 +1 내지 약 +100의 영역 내에 있는 SCN1A NIE 함유 프리-mRNA의 표적화된 부분에 상보적이다. 일부 측면에서, ASO는 포함된 엑손의 3' 스플라이스 부위에 대해 약 +1 내지 약 +90, 약 +1 내지 약 +80, 약 +1 내지 약 +70, 약 +1 내지 약 +60, 약 +1 내지 약 +50, 약 +1 내지 약 +40, 약 +1 내지 약 +30, 약 +1 내지 약 +20, 또는 약 +1 내지 약 +10의 영역 내에 있는 표적화된 부분에 상보적이다.
일부 실시양태에서, SCN1A NIE 함유 프리-mRNA의 표적화된 부분은 포함된 엑손의 5' 스플라이스 부위(3' 말단)에 대해 +100 내지 포함된 엑손의 3' 스플라이스 부위(5' 말단)에 대해 -100의 영역 내에 있다. 일부 실시양태에서, SCN1A NIE 함유 프리-mRNA의 표적화된 부분은 NIE 내에 있다. 일부 실시양태에서, SCN1A NIE 함유 프리-mRNA의 표적화된 부분은 가성 엑손과 인트론 경계를 포함한다.
ASO는 특이적 결합 및 스플라이싱의 효과적인 향상에 적합한 임의의 길이일 수 있다. 일부 실시양태에서, ASO는 8 내지 50개의 핵염기로 이루어진다. 예를 들어, ASO는 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 또는 50개의 핵염기 길이일 수 있다. 일부 실시양태에서, ASO는 50개 초과의 핵염기로 이루어진다. 일부 실시양태에서, ASO는 8 내지 50개의 핵염기, 8 내지 40개의 핵염기, 8 내지 35개의 핵염기, 8 내지 30개의 핵염기, 8 내지 25개의 핵염기, 8 내지 20개의 핵염기, 8 내지 15개의 핵염기, 9 내지 50개의 핵염기, 9 내지 40개의 핵염기, 9 내지 35개의 핵염기, 9 내지 30개의 핵염기, 9 내지 25개의 핵염기, 9 내지 20개의 핵염기, 9 내지 15개의 핵염기, 10 내지 50개의 핵염기, 10 내지 40개의 핵염기, 10 내지 35개의 핵염기, 10 내지 30개의 핵염기, 10 내지 25개의 핵염기, 10 내지 20개의 핵염기, 10 내지 15개의 핵염기, 11 내지 50개의 핵염기, 11 내지 40개의 핵염기, 11 내지 35개의 핵염기, 11 내지 30개의 핵염기, 11 내지 25개의 핵염기, 11 내지 20개의 핵염기, 11 내지 15개의 핵염기, 12 내지 50개의 핵염기, 12 내지 40개의 핵염기, 12 내지 35개의 핵염기, 12 내지 30개의 핵염기, 12 내지 25개의 핵염기, 12 내지 20개의 핵염기, 12 내지 15개의 핵염기, 13 내지 50개의 핵염기, 13 내지 40개의 핵염기, 13 내지 35개의 핵염기, 13 내지 30개의 핵염기, 13 내지 25개의 핵염기, 13 내지 20개의 핵염기, 14 내지 50개의 핵염기, 14 내지 40개의 핵염기, 14 내지 35개의 핵염기, 14 내지 30개의 핵염기, 14 내지 25개의 핵염기, 14 내지 20개의 핵염기, 15 내지 50개의 핵염기, 15 내지 40개의 핵염기, 15 내지 35개의 핵염기, 15 내지 30개의 핵염기, 15 내지 25개의 핵염기, 15 내지 20개의 핵염기, 20 내지 50개의 핵염기, 20 내지 40개의 핵염기, 20 내지 35개의 핵염기, 20 내지 30개의 핵염기, 20 내지 25개의 핵염기, 25 내지 50개의 핵염기, 25 내지 40개의 핵염기, 25 내지 35개의 핵염기, 또는 25 내지 30개의 핵염기 길이이다. 일부 실시양태에서, ASO는 18 뉴클레오티드 길이이다. 일부 실시양태에서, ASO는 15 뉴클레오티드 길이이다. 일부 실시양태에서, ASO는 25 뉴클레오티드 길이이다.
일부 실시양태에서, 상이한 화학을 가지지만 NIE 함유 프리-mRNA의 동일한 표적화된 부분에 상보적인 2개 이상의 ASO가 사용된다. 일부 실시양태에서, NIE 함유 프리-mRNA의 상이한 표적화된 부분에 상보적인 2개 이상의 ASO가 사용된다.
실시양태에서, 본 발명의 안티센스 올리고뉴클레오티드는 하나 이상의 모이어티 또는 컨쥬게이트, 예를 들어, 올리고뉴클레오티드의 활성 또는 세포 흡수를 향상시키는 표적화 모이어티 또는 다른 컨쥬게이트에 화학적으로 연결된다. 이러한 모이어티는 지질 모이어티, 예를 들어 콜레스테롤 모이어티, 콜레스테릴 모이어티, 지방족 쇄, 예를 들어 도데칸디올 또는 운데실 잔기, 폴리아민 또는 폴리에틸렌 글리콜 쇄, 또는 아다만탄 아세트산을 포함하지만, 이에 제한되지는 않는다. 친유성 모이어티를 포함하는 올리고뉴클레오티드 및 제조 방법은 공개된 문헌에 기재되어 있다. 실시양태에서, 안티센스 올리고뉴클레오티드는 무염기 뉴클레오티드, 폴리에테르, 폴리아민, 폴리아미드, 펩티드, 탄수화물, 예를 들어 N-아세틸갈락토사민(GalNAc), N-Ac-글루코사민(GluNAc), 또는 만노스(예를 들어, 만노스-6-포스페이트), 지질, 또는 다가 탄화수소 화합물을 포함하는, 그러나 이에 제한되지 않는 모이어티로 컨쥬게이트된다. 컨쥬게이트는 예를 들어 링커를 사용하여 당 업계에 이해되고 문헌에 기재된 바와 같이 당, 염기 또는 포스페이트 기 상의 임의의 여러 위치에서 안티센스 올리고뉴클레오티드를 포함하는 하나 이상의 임의의 뉴클레오티드에 연결될 수 있다. 링커는 2가 또는 3가의 분지형 링커를 포함할 수 있다. 실시양태에서, 컨쥬게이트는 안티센스 올리고뉴클레오티드의 3' 말단에 부착된다. 올리고뉴클레오티드 컨쥬게이트를 제조하는 방법은 예를 들어, 본원에 참고로 포함된 미국 특허 제8,450,467호("Carbohydrate conjugates as delivery agents for oligonucleotides")에 기술되어 있다.
일부 실시양태에서, ASO에 의해 표적화되는 핵산은 진핵 세포와 같은 세포에서 발현된 SCN1A NIE 함유 프리-mRNA이다. 일부 실시양태에서, 용어 "세포"는 세포 집단을 지칭할 수 있다. 일부 실시양태에서, 세포는 대상체에 있다. 일부 실시양태에서, 세포는 대상체로부터 단리된다. 일부 실시양태에서, 세포는 생체 외 세포이다. 일부 실시양태에서, 세포는 병태 또는 질환 관련 세포 또는 세포주이다. 일부 실시양태에서, 세포는 시험관 내 세포(예를 들어, 세포 배양물)이다.
약학 조성물
기재된 조성물의 작용제, 예를 들어 안티센스 올리고뉴클레오티드를 포함하고 기재된 임의의 방법에 사용하기 위한 약학 조성물 또는 제제는 약학 산업에 널리 공지되어 있고 공개된 문헌에 기재된 통상적인 기술에 따라 제조될 수 있다. 실시양태에서, 대상체를 치료하기 위한 약학 조성물 또는 제제는 유효량의 본원에 기재된 바와 같은 임의의 안티센스 올리고머, 또는 그의 약학적으로 허용 가능한 염, 용매화물, 수화물 또는 에스테르를 포함한다. 안티센스 올리고머를 포함하는 약학 제제는 약학적으로 허용 가능한 부형제, 희석제 또는 담체를 추가로 포함할 수 있다.
약학적으로 허용 가능한 염은 과도한 독성, 자극, 알레르기 반응 등 없이 인간 및 하등 동물의 조직과 접촉하여 사용하기에 적합하고, 합리적인 편익/위험 비에 상응한다(예를 들어, 이러한 목적을 위해 본원에 참고로 포함된 문헌[S. M. Berge, et al., J. Pharmaceutical Sciences, 66: 1-19 (1977)] 참조). 염은 화합물의 최종 단리 및 정제 중에 원위치에서 제조될 수 있거나, 유리 염기 작용기를 적합한 유기산과 반응시킴으로서 별도로 제조될 수 있다. 약학적으로 허용 가능한 비독성 산부가 염의 예는 염산, 브롬화수소산, 인산, 황산 및 과염소산과 같은 무기산, 또는 아세트산, 옥살산, 말레산, 타르타르산, 시트르산, 숙신산 또는 말론 산과 같은 유기산에 의해 또는 이온 교환과 같은 다른 문서화된 방법을 사용함으로써 형성된 아미노기의 염이다. 다른 약학적으로 허용 가능한 염은 아디페이트, 알기네이트, 아스코르베이트, 아스파테이트, 벤젠술포네이트, 벤조에이트, 비술페이트, 보레이트, 부티레이트, 캄포레이트, 캄포술포네이트, 시트레이트, 시클로펜탄프로피오네이트, 디글루코네이트, 도데실술페이트, 에탄술포네이트, 포르메이트, 푸마레이트, 글루코헵토 네이트, 글리세로포스페이트, 글루코네이트, 헤미술페이트, 헵타노에이트, 헥사노에이트, 히드로요오다이드, 2-히드록시-에탄술포네이트, 락토비오네이트, 락테이트, 라우레이트, 라우릴 술페이트, 말레이트, 말레에이트, 말로네이트, 메탄술포네이트, 2-나프탈렌술포네이트, 니코티네이트, 니트레이트, 올레에이트, 옥살레이트, 팔미테이트, 파모에이트, 펙티네이트, 퍼술페이트, 3-페닐프로피오네이트, 포스페이트, 피크레이트, 피발레이트, 프로피오네이트, 스테아레이트, 숙시네이트, 술페이트, 타르트레이트, 티오시아네이트, p-톨루엔술포네이트, 운데카노에이트, 발레레이트 염 등을 포함한다. 대표적인 알칼리 또는 알칼리 토금속 염은 나트륨, 리튬, 칼륨, 칼슘, 마그네슘 등을 포함한다. 추가의 약학적으로 허용 가능한 염에는, 적절한 경우, 할라이드, 히드록시드, 카르복실레이트, 술페이트, 포스페이트, 니레이트, 저급 알킬 술포네이트 및 아릴 술포네이트와 같은 반대 이온을 사용하여 형성된 비독성 암모늄, 4차 암모늄, 및 아민 양이온이 포함된다.
실시양태에서, 조성물은 정제, 캡슐, 겔 캡슐, 액상 시럽, 연질 겔, 좌제, 및 관장제와 같은, 그러나 이에 제한되지 않는 가능한 많은 임의의 제형으로 제제화된다. 실시양태에서, 조성물은 수성, 비수성 또는 혼합 매질에서 현탁액으로 제제화된다. 수성 현탁액은 예를 들어 소듐 카르복시메틸셀룰로스, 소르비톨 및/또는 덱스트란을 포함하여 현탁액의 점도를 증가시키는 물질을 추가로 함유할 수 있다. 현탁액은 또한 안정화제를 함유할 수 있다. 실시양태에서, 본 발명의 약학 제제 또는 조성물은 용액, 에멀젼, 마이크로에멀젼, 폼 또는 리포솜 함유 제제(예를 들어, 양이온 또는 비양이온 리포솜)을 포함하지만, 이에 제한되지는 않는다.
본원에 기재된 약학 조성물 또는 제제는 당업자에게 적절하고 널리 공지되거나 공개된 문헌에 기재된 하나 이상의 침투 증강제, 담체, 부형제 또는 다른 활성 또는 비활성 성분을 포함할 수 있다. 실시양태에서, 리포솜은 또한 입체적으로 안정화된 리포솜, 예를 들어 하나 이상의 특화된 지질을 포함하는 리포솜을 포함한다. 이러한 특화된 지질은 순환 수명이 향상된 리포솜을 생성한다. 실시양태에서, 입체적으로 안정화된 리포솜은 하나 이상의 당지질을 포함하거나 폴리에틸렌 글리콜 (PEG) 모이어티와 같은 하나 이상의 친수성 중합체로 유도체화된다. 실시양태에서, 계면활성제가 약학 제제 또는 조성물에 포함된다. 의약품, 제제 및 에멀젼에서 계면활성제의 사용은 당 업계에 잘 알려져있다. 실시양태에서, 본 발명은 안티센스 올리고뉴클레오티드의 효율적인 전달을 수행하기 위해 예를 들어 세포막을 통한 확산을 보조하고/거나 친유성 약물의 투과성을 향상시키기 위해 침투 증강제를 사용한다. 실시양태에서, 침투 증강제는 계면활성제, 지방산, 담즙 염, 킬레이트제 또는 비킬레이트 비-계면활성제이다.
실시양태에서, 약학 제제는 다중 안티센스 올리고뉴클레오티드를 포함한다. 실시양태에서, 안티센스 올리고뉴클레오티드는 다른 약물 또는 치료제와 병용하여 투여된다.
병용 요법
일부 실시양태에서, 본 개시 내용에 개시된 ASO는 하나 이상의 추가 치료제와 병용하여 사용될 수 있다. 일부 실시양태에서, 하나 이상의 추가 치료제는 소분자를 포함할 수 있다. 예를 들어, 하나 이상의 추가 치료제는 WO2016128343A1, WO2017053982A1, WO2016196386A1, WO201428459A1, WO201524876A2, WO2013119916A2, 및 WO2014209841A2에 기재된 소분자를 포함할 수 있으며, 이들은 그 전문으로 본원에 참고로 포함된다. 일부 실시양태에서, 하나 이상의 추가 치료제는 인트론 유지를 교정하는 데 사용될 수 있는 ASO를 포함한다. 일부 실시양태에서, 하나 이상의 다른 작용제는 표 1a 또는 표 1b에 열거된 ASO로부터 선택된다.
[표 1a]
Figure pct00001
Figure pct00002
[표 1b]
Figure pct00003
Figure pct00004
대상체의 치료
본원에 제공된 임의의 조성물은 개체에게 투여될 수 있다. "개체"는 "대상체" 또는 "환자"와 호환적으로 사용될 수 있다. 개체는 포유동물, 예를 들어 인간 또는 비인간 영장류, 설치류, 토끼, 랫트, 마우스, 말, 당나귀, 염소, 고양이, 개, 소, 돼지, 또는 양과 같은 동물일 수 있다. 실시양태에서, 개체는 인간이다. 실시양태에서, 개체는 태아, 배아, 또는 소아이다. 다른 실시양태에서, 개체는 식물과 같은 다른 진핵생물일 수 있다. 일부 실시양태에서, 본원에 제공된 조성물은 생체 외 세포에 투여된다.
일부 실시양태에서, 본원에 제공된 조성물은 질환 또는 장애의 치료 방법으로서 개체에게 투여된다. 일부 실시양태에서, 개체는 본원에 기재된 임의의 질환과 같은 유전 질환을 갖는다. 일부 실시양태에서, 개체는 본원에 기재된 임의의 질환과 같은 질환을 가질 위험에 있다. 일부 실시양태에서, 개체는 불충분한 단백질량 또는 단백질의 불충분한 활성에 의해 야기되는 질환 또는 장애를 가질 위험이 증가한다. 개체가 불충분한 단백질량 또는 단백질의 불충분한 활성에 의해 야기된 질환 또는 장애를 가질 "위험이 증가"한 경우, 방법은 방지 또는 예방 치료를 포함한다. 예를 들어, 개체는 질환의 가족력으로 인해 그러한 질환 또는 장애를 가질 위험이 증가할 수 있다. 전형적으로, 이러한 질환 또는 장애를 가질 위험이 증가한 개체는 예방 치료(예를 들어, 질환 또는 장애의 발병 또는 진행을 예방 또는 지연시킴으로써)가 유익하다. 실시양태에서, 태아는 예를 들어 ASO 조성물을 태아에게 직접 또는 간접적으로(예를 들어, 모체를 통해) 투여함으로써 자궁 내에서 치료된다.
본 발명의 ASO의 투여에 적합한 경로는 ASO의 전달이 바람직한 세포 유형에 따라 달라질 수 있다. 다수의 조직 및 기관은 드라벳 증후군; 열성 발작 플러스를 동반하는 전신 뇌전증 2형; 가족성 열성 발작 3A; 가족성 편마비 편두통 3; 자폐증; 조기 유아 간질성 뇌병증 13; 동기능 부전 증후군　1; 뇌가 가장 크게 이환되는 조직인 알츠하이머병 또는 SUDEP에 의해 이환된다. 본 발명의 ASO는 비경구로, 예를 들어 수막공간내 주사, 뇌실내 주사, 복강내 주사, 근육내 주사, 피하 주사, 안내 주사, 또는 정맥내 주사에 의해 환자에게 투여될 수 있다.
일부 실시양태에서, 질환 또는 병태는 Nav1.1(SCN1A 유전자에 의해 코딩된 단백질)의 돌연변이에 의해 유발된다. 일부 경우에, 돌연변이는 Nav1.1의 기능 상실 돌연변이이다. 일부 경우에, Nav1.1의 기능 상실 돌연변이는 야생형 Nav1.1의 기능에 비해 Nav1.1의 기능을 (예를 들어, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% 또는 그 이상) 감소시키거나 손상시키는 하나 이상의 돌연변이를 포함한다. 일부 경우에, Nav1.1의 기능 상실 돌연변이는 질환 표현형을 초래하는 하나 이상의 돌연변이를 포함한다. 예시적인 기능 상실 돌연변이에는 R859C, T875M, V1353L, I1656M, R1657C, A1685V, M1841T, 및 R1916G가 포함되지만 이에 제한되지는 않는다.
다른 경우에, 돌연변이는 Nav1.1의 기능 획득 돌연변이이다. 이러한 경우, 기능 획득 돌연변이는 야생형 Nav1.1의 기능에 비해 Nav1.1의 활성화를 (예를 들어, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% 또는 그 이상) 연장시키는 하나 이상의 돌연변이를 포함한다. 이러한 경우, Nav1.1의 기능 획득 돌연변이는 질환 표현형을 초래하는 하나 이상의 돌연변이를 포함한다. 예시적인 기능 획득 돌연변이에는 D188V, W1204R, R1648H, 및 D1866Y가 포함되지만 이에 제한되지는 않는다.
일부 실시양태에서, 질환 또는 병태는 뇌병증이다. 일부 경우에, 뇌병증은 Nav1.1의 기능 상실 돌연변이에 의해 유발된다.
일부 실시양태에서, 뇌병증은 간질성 뇌병증이다. 예시적인 간질성 뇌병증에는 드라벳 증후군(DS)(유아기의 중증 근간대성 뇌전증 또는 SMEI로도 알려짐); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 조기 유아 SCN1A 뇌병증; 조기 유아 간질성 뇌병증(EIEE); 또는 동기능 부전 증후군 1이 포함되지만 이에 제한되지는 않는다. 일부 실시양태에서, 질환 또는 병태는 경우에 따라 드라벳 증후군(DS)(유아기의 중증 근간대성 뇌전증 또는 SMEI로도 알려짐); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 및 동기능 부전 증후군 1로부터 선택된 간질성 뇌병증이다.
일부 경우에, GEFS+는 열성 발작 플러스를 동반하는 전신 뇌전증 2형이다.
일부 경우에, 열성 발작은 가족성 열성 발작 3A이다.
일부 경우에, SMEB는 전신 극파가 없는 SMEB(SMEB-SW), 근간대성 발작이 없는 SMEB(SMEB-M), SMEI의 하나 초과의 특징이 결여된 SMEB(SMEB-O), 또는 전신 강직성 간대 발작을 동반한 난치성 소아기 뇌전증(ICEGTC)이다.
일부 실시양태에서, Nav1.1의 기능 상실 돌연변이에 의해 유발되는 질환 또는 병태는 드라벳 증후군(DS)(SMEI로도 알려짐); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 동기능 부전 증후군 1; 조기 유아 SCN1A 뇌병증; 조기 유아 간질성 뇌병증(EIEE); 자폐증; 또는 유아기의 악성 이동 부분 발작을 포함하지만 이에 제한되지는 않는다.
일부 실시양태에서, 질환 또는 병태는 Nav1.1의 기능 획득 돌연변이에 의해 유발된다. Nav1.1의 기능 획득 돌연변이와 관련된 예시적인 질환 또는 병태는 편두통을 포함하지만 이에 제한되지는 않는다. 일부 경우에, Nav1.1의 기능 획득 돌연변이에 의해 유발되는 질환 또는 병태는 편두통이다.
일부 경우에, 편두통은 가족성 편마비 편두통 3이다.
일부 실시양태에서, 질환 또는 병태는 Nav1.1 유전성 뇌전증이다. Nav1.1 유전성 뇌전증은 Nav1.1의 기능 손실 돌연변이 또는 Nav1.1의 기능 획득 돌연변이를 포함할 수 있다. 일부 경우에, Nav1.1 유전성 뇌전증은 하나 이상의 유전 돌연변이를 포함한다. 다른 경우에, Nav1.1 유전성 뇌전증은 하나 이상의 데 노보 돌연변이를 포함한다. 일부 경우에, Nav1.1 유전성 뇌전증은 드라벳 증후군(DS)(유아기의 중증 근간대성 뇌전증 또는 SMEI로도 알려짐); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 조기 유아 SCN1A 뇌병증; 조기 유아 간질성 뇌병증(EIEE); 뇌전증에서의 돌연사(SUDEP); 또는 유아기의 악성 이동 부분 발작을 포함한다. 일부 경우에, 일부 경우에, Nav1.1의 기능 상실 돌연변이와 관련된 Nav1.1 유전성 뇌전증은 드라벳 증후군(DS)(유아기의 중증 근간대성 뇌전증 또는 SMEI로도 알려짐); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 조기 유아 SCN1A 뇌병증; 조기 유아 간질성 뇌병증(EIEE); 뇌전증에서의 돌연사(SUDEP); 유아기의 악성 이동 부분 발작을 포함한다.
일부 실시양태에서, 질환 또는 병태는 SCN1A 유전자의 반가불충분성과 관련된다. SCN1A 유전자의 반가불충분성과 관련된 예시적인 질환 또는 병태는 드라벳 증후군(DS)(SMEI로도 알려짐); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 동기능 부전 증후군 1; 조기 유아 SCN1A 뇌병증; 조기 유아 간질성 뇌병증(EIEE); 또는 유아기의 악성 이동 부분 발작을 포함하지만 이에 제한되지는 않는다. 일부 경우에, 질환 또는 병태는 드라벳 증후군(DS)(SMEI로도 알려짐); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 동기능 부전 증후군 1; 조기 유아 SCN1A 뇌병증; 조기 유아 간질성 뇌병증(EIEE); 또는 유아기의 악성 이동 부분 발작이다.
일부 경우에, 질환 또는 병태는 드라벳 증후군(DS)이다.
달리 중증의 유아기의 중증 근간대성 뇌전증(SMEI)으로 알려진 드라벳 증후군(DS)은 생후 첫 해에 나타나는 간질성 뇌병증이다. 드라벳 증후군은 환자의 약 70 내지 80%에서 나트륨 채널 유전자 돌연변이의 발견에 의해 임상 진단이 뒷받침되는 간질성 뇌병증으로 점점 더 인식되고 있다. 이온 통로 유전자의 돌연변이는 다양한 뇌전증 증후군의 발병에 중요한 역할을 하며, 이온통로병증으로 간주되는 일부 뇌전증을 초래한다. 전압 게이팅 나트륨 채널(VGSC)은 신경 흥분성에 필수적인 역할을 한다: 따라서, DS와 관련된 많은 돌연변이가 VGSC 서브유닛을 코딩하는 유전자에서 확인되었다는 것은 놀라운 일이 아니다. 이 질환은 예를 들어, 문헌(Mulley, et al., 2005) 및 OMIM #607208(Online Mendelian Inheritance in Man, Johns Hopkins University, 1966-2015)의 질환 설명에 의해 설명되며, 둘 다 본원에 참고로 포함된다.
환자의 70% 내지 80%는 나트륨 채널 α1 서브유닛 유전자(SCN1A) 이상을 보유하고, 절두 돌연변이가 약 40%를 차지하며, 이른 나이의 발작 시작과 유의한 상관관계를 갖는다. 시퀀싱 돌연변이는 약 70%의 사례에서 발견되며, 절두(40%) 및 미스센스 돌연변이(40%)를 포함하며, 나머지는 스플라이스 부위 변화이다. 대부분의 돌연변이는 드노 보이지만, 가족성 돌연변이가 5 내지 10%의 사례에서 발생하며 대개는 사실상 미스센스이다. 나머지 SCN1A 돌연변이는 스플라이스 부위 및 미스센스 돌연변이를 포함하며, 이들 대부분은 나트륨 채널의 세공 형성 영역에 속한다. 현재, 500개가 넘는 돌연변이가 DS와 관련되어 있고 유전자를 따라 무작위로 분포되어 있다(Mulley, et al., Neurol. 2006, 67, 1094-1095).
SCN1A 유전자는 인간 염색체 2q24 상의 나트륨 채널 유전자 클러스터에 위치하고 뉴런 전압 게이팅 나트륨 채널의 Nav1.1로 알려진 α-세공 형성 서브유닛을 코딩한다. SCN1A 유전자는 대략 100 kb의 게놈 DNA에 걸쳐 있으며 26개의 엑손을 포함한다. SCN1A 단백질은 각각 6개의 막 횡단 세그먼트를 갖는 4개의 도메인으로 이루어진다. 엑손 11에서 도메인 1과 2 사이의 세포질 루프에서 11개 아미노산의 존재 또는 부재에 있어 상이한 길고 짧은 아이소형을 생성하는 2개의 스플라이스 변이체가 확인되었다(Miller, et al., 1993-2015, and Mulley, et al., 2005, 25, 535-542, 본원에 참고로 포함됨).
SCN1A 유전자에서의 선택적 스플라이싱 이벤트는 비생산적 mRNA 전사체를 초래하여 결국 비정상적 단백질 발현으로 이어질 수 있으며, SCN1A 유전자에서 선택적 스플라이싱 이벤트를 표적화할 수 있는 치료제는 DS 환자에서 기능성 단백질의 발현 수준을 조절하고/거나 비정상적 단백질 발현을 억제할 수 있다. 이러한 치료제는 SCN1A 단백질 결핍에 의해 야기된 병태를 치료하는 데 사용될 수 있다.
비생산적인 mRNA 전사체를 초래할 수 있는 선택적 스플라이싱 이벤트 중 하나는 넌센스 매개 mRNA 붕괴를 유도할 수 있는 mRNA 전사체에 추가의 엑손을 포함시키는 것이다. 본 개시 내용은 단백질을 코딩하는 성숙한 mRNA의 생성을 증가시켜 번역된 기능성 SCN1A 단백질을 증가시키기 위해 SCN1A의 선택적 스플라이싱을 조절하기 위한 조성물 및 방법을 제공한다. 이들 조성물 및 방법은 엑손 스키핑을 야기하고 SCN1A 프리-mRNA의 구성적 스플라이싱을 촉진할 수 있는 안티센스 올리고머(ASO)를 포함한다. 다양한 실시양태에서, SCN1A 단백질 결핍에 의해 야기된 병태를 치료하기 위해 본 개시 내용의 방법을 사용하여 기능성 SCN1A 단백질을 증가시킬 수 있다.
일부 경우에, 질환 또는 병태는 SMEB이다.
일부 경우에, 질환 또는 병태는 GEFS+이다.
일부 경우에, 질환 또는 병태는 열성 발작(예를 들어, 가족성 열성 발작 3A)이다.
일부 경우에, 질환 또는 병태는 자폐증(자폐 스펙트럼 장애 또는 ASD로도 알려짐)이다.
일부 경우에, 질환 또는 병태는 편두통(예를 들어, 가족성 편마비 편두통 3)이다.
일부 경우에, 질환 또는 병태는 알츠하이머병이다.
일부 실시양태에서, 질환 또는 병태는 SCN2A 뇌병증이다.
일부 실시양태에서, 질환 또는 병태는 SCN8A 뇌병증이다.
일부 실시양태에서, 질환 또는 병태는 SCN5A 부정맥이다.
실시양태에서, 안티센스 올리고뉴클레오티드는 당 업계에 공지된 임의의 방법에 의해 혈액-뇌 장벽을 통한 본 안티센스 올리고뉴클레오티드의 침투를 촉진할 수 있는 하나 이상의 작용제와 함께 투여된다. 예를 들어, 근육 조직에서 운동 뉴런으로 아데노 바이러스 벡터의 투여에 의한 작용제의 전달이 미국 특허 제6,632,427호("Adenoviral-vector-mediated gene transfer into medullary motor neurons", 본원에 참고로 포함됨)에 기재되어 있다. 뇌, 예를 들어 선조, 시상, 해마 또는 흑질로 직접적인 벡터의 전달이, 예를 들어 미국 특허 제6,756,523호("Adenovirus vectors for the transfer of foreign genes into cells of the central nervous system particularly in brain", 본원에 참고로 포함됨)에 기재되어 있다.
실시양태에서, 안티센스 올리고뉴클레오티드는 바람직한 약학적 또는 약력 학적 특성을 제공하는 작용제와 연결되거나 컨쥬게이트된다. 실시양태에서, 안티센스 올리고뉴클레오티드는 혈액-뇌 장벽를 통한 침투 또는 수송을 촉진하기 위해 당 업계에 공지된 물질, 예를 들어 트랜스페린 수용체에 대한 항체에 커플링된다. 실시양태에서, 안티센스 올리고뉴클레오티드는 바이러스 벡터와 연결되어, 예를 들어 안티센스 화합물을 더 효과적으로 만들거나 혈액-뇌 장벽을 통한 수송을 증가시킨다. 실시양태에서, 삼투성 혈액 뇌 장벽 파괴는 당, 예를 들어 메조 에리트리톨, 자일리톨, D(+) 갈락토오스, D(+) 락토오스, D(+) 자일로스, 둘시톨, 미오-이노시톨, L(-) 프룩토오스, D(-) 만니톨, D(+) 글루코오스, D(+) 아라비노스, D(-) 아라비노오스, 셀로비오스, D(+) 말토오스, D(+) 라피노스, L(+) 람노오스, D(+) 멜리비오스, D(-) 리보오스, 아도니톨, D(+) 아라비톨, L(-) 아라비톨, D(+) 푸코오스, L(-) 푸코오스, D(-) 릭소오스, L(+) 릭소오스, 및 L(-) 릭소오스, 또는 아미노산, 예를 들어 글루타민, 리신, 아르기닌, 아스파라긴, 아스파르트산, 시스테인, 글루탐산, 글리신, 히스티딘, 류신, 메티오닌, 페닐알라닌, 프롤린, 세린, 트레오닌, 티로신, 발린, 및 타우린의 주입에 의해 보조받는다. 혈액 뇌 장벽 침투를 향상시키기 위한 방법 및 물질은, 예를 들어 미국 특허 제9,193,969호("Compositions and methods for selective delivery of oligonucleotide molecules to specific neuron types"), 미국 특허 제4,866,042호("Method for the delivery of genetic material across the blood brain barrier"), 미국 특허 제6,294,520호("Material for passage through the blood-brain barrier"), 및 미국 특허 제6,936,589호("Parenteral delivery systems")에 기술되어 있으며, 이들 각각은 본원에 참고로 포함된다.
실시양태에서, 본 발명의 ASO는 예를 들어 본원에 참고로 포함된 미국 특허 제9,193,969호에 기재된 방법을 사용하여 도파민 재흡수 억제제(DRI), 선택적 세로토닌 재흡수 억제제(SSRI), 노르아드레날린 재흡수 억제제(NRI), 노르에피네프린-도파민 재흡수 억제제(NDRI), 및 세로토닌-노르에피네프린-도파민 재흡수 억제제(SNDRI)에 커플링된다.
실시양태에서, 방법 및 조성물을 사용하여 치료된 대상체는 당 업계에 공지되고 설명된 임의의 방법을 사용하여 병태의 개선에 대해 평가된다.
엑손 스키핑을 유도하는 추가 ASO 확인 방법
SCN1A NIE 함유 프리-mRNA의 엑손 스키핑을 유도하는 ASO를 확인 또는 결정하기 위한 방법이 또한 본 발명의 범위 내에 있다. 예를 들어, 방법은 SCN1A NIE 함유 프리-mRNA의 가성 엑손 스키핑을 유도하는 ASO를 확인 또는 결정하는 단계를 포함할 수 있다. 프리-mRNA의 표적 영역 내의 상이한 뉴클레오티드에 특이적으로 혼성화하는 ASO를 스크리닝하여 표적 인트론의 스플라이싱 속도 및/또는 정도를 개선시키는 ASO를 확인 또는 결정할 수 있다. 일부 실시 형태에서, ASO는 스플라이싱 억제제(들)/사일런서의 결합 부위(들)를 차단하거나 방해할 수 있다. 당해 기술 분야에 공지된 임의의 방법을 사용하여 엑손의 표적 영역에 혼성화될 때 원하는 효과(예를 들어, 가성 엑손 스키핑, 단백질 또는 기능성 RNA 생성)를 초래하는 ASO를 확인(결정)할 수 있다. 또한, 이들 방법을 사용하여 포함된 엑손 측면에 위치한 인트론 또는 포함되지 않은 엑손 내 표적화된 영역에 결합함으로써 포함된 엑손의 엑손 스키핑를 유도하는 ASO를 확인할 수 있다. 사용될 수 있는 방법의 예는 아래에 제공된다.
프리-mRNA의 표적 영역에 혼성화하도록 설계된 ASO를 사용하여 ASO "워크"로 지칭되는 한 라운드의 스크리닝이 수행될 수 있다. 예를 들어, ASO 워크에 사용된 ASO는 포함된 엑손의 3' 스플라이스 부위의 대략 100 뉴클레오티드 상류(예를 들어, 표적/포함된 엑손의 상류에 위치한 엑손 서열의 일부)부터 표적/포함된 엑손의 3' 스플라이스 부위의 약 100 뉴클레오티드 하류까지 및/또는 포함된 엑손의 5' 스플라이스 부위의 약 100 뉴클레오티드 상류부터 표적/포함된 엑손의 5' 스플라이스 부위의 약 100 뉴클레오티드 하류(예를 들어, 표적/포함된 엑손의 하류에 위치한 엑손의 서열의 일부)까지 5 뉴클레오티드마다 타일링될 수 있다. 예를 들어, 15 뉴클레오티드 길이의 제1 ASO는 표적/포함된 엑손의 3' 스플라이스 부위에 대해 뉴클레오티드 +6 내지 +20에 특이적으로 혼성화하도록 설계될 수 있다. 제2 ASO는 표적/포함된 엑손의 3'스플라이스 부위에 대해 뉴클레오티드 +11 내지 +25에 특이적으로 혼성화하도록 설계될 수 있다. ASO는 프리-mRNA의 표적 영역에 이렇게 걸쳐있는 것으로 설계된다. 실시양태에서, ASO는 예를 들어 1, 2, 3 또는 4 뉴클레오티드마다 더 가까이 타일링될 수 있다. 또한, ASO는 5' 스플라이스 부위의 100 뉴클레오티드 하류부터 3' 스플라이스 부위의 100 뉴클레오티드 상류에 타일링될 수 있다. 일부 실시양태에서, ASO는 3' 스플라이스 부위의 약 1,160 뉴클레오티드 상류부터 5'스플라이스 부위의 약 500 뉴클레오티드 하류에 타일링될 수 있다. 일부 실시양태에서, ASO는 3' 스플라이스 부위의 약 500 뉴클레오티드 상류부터 3' 스플라이스 부위의 약 1,920 뉴클레오티드 하류에 타일링될 수 있다.
하나 이상의 ASO, 또는 대조군 ASO(표적 영역에 혼성화하지 않을 것으로 예상되는 서열인 스크램블링된 서열을 갖는 ASO)는, 예를 들어 형질 감염에 의해, 표적 프리-mRNA(예를 들어, 본원에 기재된 NIE 함유 프리-mRNA)을 발현하는 질환 관련 세포주 내로 전달된다. 각각의 ASO의 엑손 스키핑 효과는 당 업계에 공지된 임의의 방법, 예를 들어 실시예 4에 기재된 바와 같이 스플라이스 접합부에 걸쳐있는 프라이머를 사용하는 역전사 효소(RT)-PCR에 의해 평가될 수 있다. 대조군 ASO 처리된 세포와 비교하여 ASO 처리된 세포에서 포함된 엑손(예를 들어, NIE의 측면 엑손 포함)을 함유하는 영역에 걸친 프라이머를 사용하여 생성된 더 긴 RT-PCR 생성물의 감소 또는 부재는 표적 NIE의 스플라이싱이 향상되었음을 나타낸다. 일부 실시양태에서, 엑손 스키핑 효율(또는 NIE를 함유하는 인트론을 스플라이싱하는 스플라이싱 효율), 스플라이싱되지 않은 프리-mRNA에 대한 스플라이싱된 프리-mRNA의 비율, 스플라이싱 속도 또는 스플라이싱 정도는 본원에 기재된 ASO를 사용하여 개선될 수 있다. 또한, 표적 프리-mRNA에 의해 코딩되는 단백질 또는 기능성 RNA의 양을 평가하여 각각의 ASO가 원하는 효과(예를 들어, 기능성 단백질 생산의 향상)를 달성했는지를 결정할 수 있다. 웨스턴 블롯팅, 유세포 분석, 면역 형광 현미경법, 및 ELISA와 같은 단백질 생산을 평가 및/또는 정량하기 위해 당 업계에 공지된 임의의 방법이 사용될 수 있다.
프리-mRNA의 표적 영역에 혼성화하도록 설계된 ASO를 사용하여 ASO "마이크로 워크"라고 불리는 제2 라운드의 스크리닝을 수행할 수 있다. ASO 마이크로 워크에 사용된 ASO를 1 뉴클레오티드마다 타일링하여 ASO와 혼성화될 때 엑손 스키핑(또는 NIE의 향상된 스플라이싱)을 초래하는 프리-mRNA의 뉴클레오티드 서열을 추가로 정제(refine)한다.
표적 인트론의 스플라이싱을 촉진하는 ASO에 의해 정의된 영역은 1-nt 스텝 간격의 ASO뿐만 아니라 더 긴 ASO, 전형적으로 18 내지 25 nt를 포함하는 ASO "마이크로 워크"에 의해 더 상세하게 탐색된다.
상기 ASO 워크에 대해 설명된 바와 같이, 하나 이상의 ASO, 또는 대조군 ASO(표적 영역에 혼성화할 것으로 예상되지 않는 서열인 스크램블링된 서열을 갖는 ASO)를, 예를 들어 형질 감염에 의해, 표적 프리-mRNA를 발현하는 질환 관련 세포주 내로 전달하여 ASO 마이크로 워크를 수행한다. 각각의 ASO의 스플라이싱 유도 효과는 당 업계에 공지된 임의의 방법, 예를 들어 본원에 기재된 바와 같이 NIE에 걸친 프라이머를 사용하는 역전사 효소(RT)-PCR에 의해 평가될 수 있다(예를 들어, 실시예 4 참조). 대조군 ASO 처리된 세포와 비교하여 ASO 처리된 세포에서 NIE에 걸친 프라이머를 사용하여 생성된 더 긴 RT-PCR 생성물의 감소 또는 부재는 엑손 스키핑(또는 NIE를 함유하는 표적 인트론의 스플라이싱)이 향상되었음을 나타낸다. 일부 실시양태에서, 엑손 스키핑 효율(또는 NIE를 함유하는 인트론을 스플라이싱하는 스플라이싱 효율), 스플라이싱되지 않은 것에 대한 스플라이싱된 프리-mRNA의 비율, 스플라이싱 속도 또는 스플라이싱 정도는 본원에 기재된 ASO를 사용하여 개선될 수 있다. 또한, 표적 프리-mRNA에 의해 코딩되는 단백질 또는 기능성 RNA의 양을 평가하여 각각의 ASO가 원하는 효과(예를 들어, 기능성 단백질 생산의 향상)를 달성했는지를 결정할 수 있다. 웨스턴 블롯팅, 유세포 분석, 면역 형광 현미경법 및 ELISA와 같은 단백질 생산을 평가 및/또는 정량하기 위해 당 업계에 공지된 임의의 방법이 사용될 수 있다.
프리-mRNA의 영역에 혼성화될 때 엑손 스키핑(또는 NIE를 함유하는 인트론의 스플라이싱 향상) 및 단백질 생산 증가를 초래하는 ASO는 동물 모델, 예를 들어 전장 인간 유전자가 녹인된 트랜스제닉 마우스 모델을 사용하여 또는 질환의 인간화된 마우스 모델에서 생체 내에서 시험될 수 있다. ASO의 투여를 위한 적절한 경로는 질환 및/또는 ASO의 전달이 요구되는 세포 유형에 따라 달라질 수 있다. ASO는 예를 들어 수막공간내 주사, 뇌실내 주사, 복강내 주사, 근육내 주사, 피하 주사, 안내 주사, 또는 정맥내 주사에 의해 투여될 수 있다. 투여 후, 모델 동물의 세포, 조직, 및/또는 기관은 예를 들어 당 업계에 공지되고 본원에 기재된 방법에 의해 스플라이싱(효율, 속도, 정도) 및 단백질 생산을 평가함으로써 ASO 처리의 효과를 결정하기 위해 평가될 수 있다. 동물 모델은 또한 질환 또는 질환 중증도의 표현형 또는 행동을 나타낼 수 있다.
다양한 예에서 본원에 기술된 바와 같이, 인간 SCN1A 유전자의 엑손 20x는 마우스 SCN1A 유전자의 엑손 21x와 동등하다.
또한, NMD 억제제, 예를 들어 시클로헥시미드의 존재 하에 NMD 유도 엑손을 식별 또는 확인하는 방법이 본 발명의 범위 내에 있다. 예시적인 방법이 [도 3] 및 실시예 2에 제공된다.
구체적인 실시양태
실시양태 1. SCN1A 단백질을 코딩하는, 넌센스 매개 RNA 붕괴 유도 엑손을 함유하는 mRNA(NMD 엑손 mRNA)를 갖는 세포에서 SCN1A 단백질의 발현을 조절하는 방법으로서, 치료제를 세포에 접촉시키는 단계를 포함하고, 그로 인하여 치료제가 SCN1A 단백질을 코딩하는 NMD 엑손 mRNA로부터 NMD 엑손의 스플라이싱을 조절하고, 이로써 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 조절하고, SCN1A 단백질의 발현을 조절하는 것인 방법.
실시양태 2. 치료를 필요로 하는 대상체의 세포에서 SCN1A 단백질의 발현을 조절함으로써 대상체에서 질환 또는 병태를 치료하는 방법으로서, 대상체의 세포를 NMD 엑손을 함유하고 SCN1A를 코딩하는 세포에서 mRNA로부터 넌센스 매개 mRNA 붕괴 유도 엑손(NMD 엑손)의 스플라이싱을 조절하는 치료제와 접촉시키는 단계를 포함하고, 그로 인하여 대상체의 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 조절하고, SCN1A 단백질의 발현을 조절하는 것인 방법.
실시양태 3. 실시양태 1 또는 2에 있어서, 치료제는
(a) SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 결합하거나;
(b) NMD 엑손 mRNA의 스플라이싱에 관여하는 인자의 결합을 조절하거나;
(c) (a)와 (b)의 조합인 방법.
실시양태 4. 실시양태 3에 있어서, 치료제는 표적화된 부분의 영역으로부터 NMD 엑손의 스플라이싱에 관여하는 인자의 결합을 방해하는 것인 방법.
실시양태 5. 실시양태 3 또는 4에 있어서, 표적화된 부분은 NMD 엑손에 근접한 것인 방법.
실시양태 6. 실시양태 3 내지 5 중 어느 하나에 있어서, 표적화된 부분은 NMD 엑손의 5' 말단의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 상류에 있는 것인 방법.
실시양태 7. 실시양태 3 내지 6 중 어느 하나에 있어서, 표적화된 부분은 NMD 엑손의 5' 말단의 적어도 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 상류에 있는 것인 방법.
실시양태 8. 실시양태 3 내지 5 중 어느 하나에 있어서, 표적화된 부분은 NMD 엑손의 3' 말단의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 하류에 있는 것인 방법.
실시양태 9. 실시양태 3 내지 5 또는 8 중 어느 하나에 있어서, 표적화된 부분은 NMD 엑손의 3' 말단의 적어도 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 하류에 있는 것인 방법.
실시양태 10. 실시양태 3 내지 9 중 어느 하나에 있어서, 표적화된 부분은 SCN1A를 코딩하는 NMD 엑손 mRNA의 2개의 표준 엑손 영역 사이의 인트론 영역에 위치하며, 인트론 영역은 NMD 엑손을 함유하는 것인 방법.
실시양태 11. 실시양태 3 내지 10 중 어느 하나에 있어서, 표적화된 부분은 NMD 엑손과 적어도 부분적으로 중첩되는 것인 방법.
실시양태 12. 실시양태 3 내지 11 중 어느 하나에 있어서, 표적화된 부분은 NMD 엑손의 상류 인트론과 적어도 부분적으로 중첩되는 것인 방법.
실시양태 13. 실시양태 3 내지 12 중 어느 하나에 있어서, 표적화된 부분은 5' NMD 엑손-인트론 접합부 또는 3' NMD 엑손-인트론 접합부를 포함하는 것인 방법.
실시양태 14. 실시양태 3 내지 13 중 어느 하나에 있어서, 표적화된 부분은 NMD 엑손 내에 있는 것인 방법.
실시양태 15. 실시양태 3 내지 14 중 어느 하나에 있어서, 표적화된 부분은 NMD 엑손의 약 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30개 또는 그 이상의 연속적인 뉴클레오티드를 포함하는 것인 방법.
실시양태 16. 실시양태 1 내지 15 중 어느 하나에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA는 서열 번호 2 또는 7 내지 10 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함하는 것인 방법.
실시양태 17. 실시양태 1 내지 16 중 어느 하나에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA는 서열 번호 1 또는 3 내지 6과 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 유전자 서열에 의해 코딩되는 것인 방법.
실시양태 18. 실시양태 3 내지 17 중 어느 하나에 있어서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,803의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 상류에 있는 것인 방법.
실시양태 19. 실시양태 3 내지 18 중 어느 하나에 있어서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,803의 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 상류에 있는 것인 방법.
실시양태 20. 실시양태 3 내지 17 중 어느 하나에 있어서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,740의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 하류에 있는 것인 방법.
실시양태 21. 실시양태 3 내지 17 또는 20 중 어느 하나에 있어서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,740의 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 하류에 있는 것인 방법.
실시양태 22. 실시양태 3 내지 21 중 어느 하나에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 서열 번호 2 또는 7 내지 10의 적어도 8개의 인접한 핵산을 포함하는 영역과 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함하는 것인 방법.
실시양태 23. 실시양태 22에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21 내지 67, 210 내지 256, 또는 304 내지 379 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 24. 실시양태 3 내지 21 중 어느 하나에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x 내에 있는 것인 방법.
실시양태 25. 실시양태 24에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 42 내지 50, 또는 231 내지 239 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 26. 실시양태 3 내지 21 중 어느 하나에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x의 상류 또는 하류에 있는 것인 방법.
실시양태 27. 실시양태 26에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21 내지 38, 53 내지 67, 210 내지 227, 또는 242 내지 256 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 28. 실시양태 3 내지 21 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 엑손 20x의 엑손-인트론 접합부를 포함하는 것인 방법.
실시양태 29. 실시양태 28에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 39 내지 41, 51, 52, 228 내지 230, 240, 또는 241 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 30. 실시양태 1 내지 29 중 어느 하나에 있어서, 치료제는 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 촉진하는 것인 방법.
실시양태 31. 실시양태 30에 있어서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제는 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제와 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가하는 것인 방법.
실시양태 32. 실시양태 30 또는 31에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 증가시키는 것인 방법.
실시양태 33. 실시양태 30 내지 32 중 어느 하나에 있어서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 양은 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가하는 것인 방법.
실시양태 34. 실시양태 30 내지 33 중 어느 하나에 있어서, 치료제는 세포에서 SCN1A 단백질의 발현을 증가시키는 것인 방법.
실시양태 35. 실시양태 30 내지 34 중 어느 하나에 있어서, 치료제와 접촉된 세포에서 생성된 SCN1A의 양은 대조군 세포에서 생성된 SCN1A의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가하는 것인 방법.
실시양태 36. 실시양태 2 내지 35 중 어느 하나에 있어서, 질환 또는 병태는 Nav1.1의 기능 상실 돌연변이에 의해 유발되는 것인 방법.
실시양태 37. 실시양태 2 내지 36 중 어느 하나에 있어서, 질환 또는 병태는 SCN1A 유전자의 반가불충분성과 관련되며, 대상체는 기능성 SCN1A를 코딩하는 제1 대립 유전자, 및 SCN1A가 생성되지 않거나 감소한 수준으로 생성되는 제2 대립 유전자, 또는 비기능성 SCN1A 또는 부분 기능성 SCN1A를 코딩하는 제2 대립 유전자를 갖는 것인 방법.
실시양태 38. 실시양태 2 내지 37 중 어느 하나에 있어서, 질환 또는 병태는 뇌병증인 방법.
실시양태 39. 실시양태 38에 있어서, 뇌병증은 간질성 뇌병증인 방법.
실시양태 40. 실시양태 2 내지 37 중 어느 하나에 있어서, 질환 또는 병태는 드라벳 증후군(DS); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 동기능 부전 증후군 1; 자폐증; 또는 유아기의 악성 이동 부분 발작인 방법.
실시양태 41. 실시양태 40에 있어서, GEFS+는 열성 발작 플러스를 동반하는 전신 뇌전증 2형인 방법.
실시양태 42. 실시양태 40에 있어서, 열성 발작은 가족성 열성 발작 3A인 방법.
실시양태 43. 실시양태 40에 있어서, SMEB는 전신 극파가 없는 SMEB(SMEB-SW), 근간대성 발작이 없는 SMEB(SMEB-M), SMEI의 하나 초과의 특징이 결여된 SMEB(SMEB-O), 또는 전신 강직성 간대 발작을 동반한 난치성 소아기 뇌전증(ICEGTC)인 방법.
실시양태 44. 실시양태 1 내지 43 중 어느 하나에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 촉진하고 SCN1A의 발현을 증가시키는 것인 방법.
실시양태 45. 실시양태 1 내지 44 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 22 내지 24, 26, 27, 29 내지 35, 37 내지 62, 64 내지 67, 또는 304 내지 379 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함하는 것인 방법.
실시양태 46. 실시양태 1 내지 29 중 어느 하나에 있어서, 치료제는 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 억제하는 것인 방법.
실시양태 47. 실시양태 46에 있어서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제는 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제와 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소하는 것인 방법.
실시양태 48. 실시양태 46 또는 47에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 감소시키는 것인 방법.
실시양태 49. 실시양태 46 내지 48 중 어느 하나에 있어서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 양은 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소하는 것인 방법.
실시양태 50. 실시양태 46 내지 49 중 어느 하나에 있어서, 치료제는 세포에서 SCN1A 단백질의 발현을 감소시키는 것인 방법.
실시양태 51. 실시양태 46 내지 50 중 어느 하나에 있어서, 치료제와 접촉된 세포에서 생성된 SCN1A의 양은 대조군 세포에서 생성된 SCN1A의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소하는 것인 방법.
실시양태 52. 실시양태 2 내지 29 또는 46 내지 49 중 어느 하나에 있어서, 질환 또는 병태는 Nav1.1의 기능 획득 돌연변이에 의해 유발되는 것인 방법.
실시양태 53. 실시양태 52에 있어서, 대상체는 세포에서 SCN1A가 증가한 수준으로 생성되는 대립 유전자, 또는 Nav1.1의 증가한 활성을 유도하는 돌연변이 SCN1A를 코딩하는 대립 유전자를 갖는 것인 방법.
실시양태 54. 실시양태 52 또는 53에 있어서, 질환 또는 병태는 편두통인 방법.
실시양태 55. 실시양태 54에 있어서, 편두통은 가족성 편마비 편두통 3인 방법.
실시양태 56. 실시양태 2 내지 49 중 어느 하나에 있어서, 질환 또는 병태는 Nav1.1 유전성 뇌전증인 방법.
실시양태 57. 실시양태 46 내지 56 중 어느 하나에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 억제하고 SCN1A의 발현을 감소시키는 것인 방법.
실시양태 58. 실시양태 46 내지 57 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21, 25, 28, 36, 또는 63 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함하는 것인 방법.
실시양태 59. 실시양태 1 내지 58 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로티오에이트 결합 또는 포스포로디아미데이트 결합을 포함하는 백본 변형을 포함하는 것인 방법.
실시양태 60. 실시양태 1 내지 59 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로디아미데이트 모르폴리노, 잠금 핵산, 펩티드 핵산, 2'-O-메틸, 2'-플루오로, 또는 2'-O-메톡시에틸 모이어티를 포함하는 것인 방법.
실시양태 61. 실시양태 1 내지 60 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 하나 이상의 변형된 당 모이어티를 포함하는 것인 방법.
실시양태 62. 실시양태 61에 있어서, 각각의 당 모이어티는 변형된 당 모이어티인 방법.
실시양태 63. 실시양태 1 내지 62 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 8 내지 50개의 핵염기, 8 내지 40개의 핵염기, 8 내지 35개의 핵염기, 8 내지 30개의 핵염기, 8 내지 25개의 핵염기, 8 내지 20개의 핵염기, 8 내지 15개의 핵염기, 9 내지 50개의 핵염기, 9 내지 40개의 핵염기, 9 내지 35개의 핵염기, 9 내지 30개의 핵염기, 9 내지 25개의 핵염기, 9 내지 20개의 핵염기, 9 내지 15개의 핵염기, 10 내지 50개의 핵염기, 10 내지 40개의 핵염기, 10 내지 35개의 핵염기, 10 내지 30개의 핵염기, 10 내지 25개의 핵염기, 10 내지 20개의 핵염기, 10 내지 15개의 핵염기, 11 내지 50개의 핵염기, 11 내지 40개의 핵염기, 11 내지 35개의 핵염기, 11 내지 30개의 핵염기, 11 내지 25개의 핵염기, 11 내지 20개의 핵염기, 11 내지 15개의 핵염기, 12 내지 50개의 핵염기, 12 내지 40개의 핵염기, 12 내지 35개의 핵염기, 12 내지 30개의 핵염기, 12 내지 25개의 핵염기, 12 내지 20개의 핵염기, 또는 12 내지 15개의 핵염기로 이루어지는 것인 방법.
실시양태 64. 실시양태 3 내지 63 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 단백질을 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 98%, 적어도 99%, 또는 100% 상보적인 것인 방법.
실시양태 65. 실시양태 1 내지 64 중 어느 하나에 있어서, SCN1A mRNA 또는 단백질 발현을 평가하는 단계를 추가로 포함하는 방법.
실시양태 66. 실시양태 2 내지 65 중 어느 하나에 있어서, 대상체는 인간인 방법.
실시양태 67. 실시양태 2 내지 65 중 어느 하나에 있어서, 대상체는 비인간 동물인 방법.
실시양태 68. 실시양태 2 내지 65 중 어느 하나에 있어서, 대상체는 태아, 배아, 또는 소아인 방법.
실시양태 69. 실시양태 1 내지 68 중 어느 하나에 있어서, 세포는 생체 외 세포인 방법.
실시양태 70. 실시양태 2 내지 69 중 어느 하나에 있어서, 치료제는 대상체의 수막공간내 주사, 뇌실내 주사, 복강내 주사, 근육내 주사, 피하 주사, 안내, 또는 정맥내 주사에 의해 투여되는 것인 방법.
실시양태 71. 실시양태 2 내지 65 중 어느 하나에 있어서, 대상체에게 제2 치료제를 투여하는 단계를 추가로 포함하는 방법.
실시양태 72. 실시양태 71에 있어서, 제2 치료제는 소분자인 방법.
실시양태 73. 실시양태 71에 있어서, 제2 치료제는 ASO인 방법.
실시양태 74. 실시양태 73에 있어서, ASO는 서열 번호 115 내지 161 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함하는 것인 방법.
실시양태 75. 실시양태 71에 있어서, 제2 치료제는 인트론 유지를 교정하는 것인 방법.
실시양태 76. 실시양태 2 내지 65 중 어느 하나에 있어서, 질환 또는 병태는 알츠하이머병, SCN2A 뇌병증, SCN8A 뇌병증, 또는 SCN5A 부정맥인 방법.
실시양태 77. 실시양태 30, 32 또는 34 중 어느 하나에 있어서, 질환 또는 병태는 알츠하이머병, SCN2A 뇌병증, SCN8A 뇌병증, 또는 SCN5A 부정맥인 방법.
실시양태 78. 드라벳 증후군(DS); 열성 발작 플러스를 동반하는 전신 뇌전증 2형; 가족성 열성 발작 3A; 가족성 편마비 편두통 3; 자폐증; 조기 유아 간질성 뇌병증 13; 동기능 부전 증후군 1; 알츠하이머병 또는 뇌전증에서의 돌연사(SUDEP)의 치료를 필요로 하는 대상체의 세포에 의한 표적 단백질 또는 기능성 RNA의 발현을 증가시킴으로써 대상체에서 이를 치료하는 방법으로서, 세포는 넌센스 매개 RNA 붕괴 유도 엑손를 함유하는 mRNA(NMD 엑손 mRNA)를 가지며, NMD 엑손 mRNA는 표적 단백질 또는 기능성 RNA를 코딩하며, 대상체의 세포를 표적 단백질 또는 기능성 RNA를 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 결합하는 치료제와 접촉시킴으로써, 넌센스 매개 RNA 붕괴 유도 엑손이 표적 단백질 또는 기능성 RNA를 코딩하는 NMD 엑손 mRNA로부터 배제되어, 이로써 대상체의 세포에서 표적 단백질 또는 기능성 RNA를 코딩하는 가공된 mRNA의 수준을 증가시키고, 표적 단백질 또는 기능성 RNA의 발현을 증가시키는 단계를 포함하는 방법.
실시양태 79. 실시양태 78에 있어서, 표적 단백질은 SCN1A인 방법.
실시양태 80. 넌센스 매개 NA 붕괴 유도 엑손을 함유하고(NMD 엑손 mRNA) SCN1A 단백질을 코딩하는 mRNA를 가진 세포에 의한 SCN1A 단백질의 발현을 증가시키는 방법으로서, 세포를 SCN1A 단백질을 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 결합하는 작용제와 접촉시키는 단계를 포함하고, 그로 인하여 넌센스 매개 RNA 붕괴 유도 엑손이 SCN1A 단백질을 코딩하는 NMD 엑손 mRNA로부터 배제되고, 이로써 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 증가시키고, SCN1A 단백질의 발현을 증가시키는 것인 방법.
실시양태 81. 질환 또는 병태의 치료를 필요로 하는 대상체의 세포에서 SCN1A 단백질의 발현을 증가시킴으로써 대상체에서 질환 또는 병태를 치료하는 방법으로서, 대상체의 세포를 SCN1A 단백질 또는 기능성 SCN1A RNA를 코딩하는 넌센스 매개 RNA 붕괴 유도 엑손 mRNA의 표적화된 부분에 결합하는 치료제와 접촉시키는 단계를 포함하고, 그로 인하여 넌센스 매개 RNA 붕괴 유도 엑손이 SCN1A 단백질 또는 기능성 SCN1A RNA를 코딩하는 NMD 엑손 mRNA로부터 배제되고, 이로써 대상체의 세포에서 SCN1A 단백질 또는 기능성 SCN1A RNA를 코딩하는 가공된 mRNA의 수준을 증가시키고, SCN1A 단백질 또는 기능성 SCN1A RNA의 발현을 증가시키며; 질환 또는 병태는 SCN1A 유전자 이외의 유전자의 돌연변이, SCN1A 유전자 이외의 유전자에 의해 코딩된 단백질의 비정상적 발현 또는 SCN1A 유전자 이외의 유전자에 의해 코딩된 RNA의 비정상적 발현과 관련되는 것인 방법.
실시양태 82. 실시양태 81에 있어서, 질환 또는 병태의 증상은 약 2배, 3배, 4배, 5배, 6배, 7배, 8배, 9배, 10배 또는 그 이상 감소하는 것인 방법.
실시양태 83. 실시양태 81 또는 82에 있어서, 질환 또는 병태의 증상은 SCN1A 단백질의 발현 증가에 의해 약 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 또는 100% 감소하는 것인 방법.
실시양태 84. 실시양태 81 내지 83 중 어느 하나에 있어서, 질환 또는 병태의 진행은 SCN1A 단백질의 발현 증가에 의해 약 2배, 3배, 4배, 5배, 6배, 7배, 8배, 9배, 10배 또는 그 이상 감소하는 것인 방법.
실시양태 85. 실시양태 81 내지 84 중 어느 하나에 있어서, 질환 또는 병태의 진행은 SCN1A 단백질의 발현 증가에 의해 약 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 또는 100% 감소하는 것인 방법.
실시양태 86. 실시양태 81 내지 85 중 어느 하나에 있어서, SCN1A 단백질 또는 기능성 SCN1A RNA의 발현을 증가시키는 단계는 SCN1A 유전자 이외의 유전자의 돌연변이, SCN1A 유전자 이외의 유전자에 의해 코딩된 단백질의 비정상적 발현 또는 SCN1A 유전자 이외의 유전자에 의해 코딩된 RNA의 비정상적 발현을 보상하는 것인 방법.
실시양태 87. 실시양태 81 내지 86 중 어느 하나에 있어서, 질환 또는 병태는 조기 유아 간질성 뇌병증 13인 방법.
실시양태 88. 실시양태 81 내지 87 중 어느 하나에 있어서, 대상체는 SCN8A 유전자에 돌연변이를 갖는 것인 방법.
실시양태 89. 실시양태 81 내지 86 중 어느 하나에 있어서, 질환 또는 병태는 동기능 부전 증후군 1인 방법.
실시양태 90. 실시양태 81 내지 86 또는 88 중 어느 하나에 있어서, 대상체는 SCN5A 유전자에 돌연변이를 갖는 것인 방법.
실시양태 91. 실시양태 81 내지 86 중 어느 하나에 있어서, 질환 또는 병태는 알츠하이머병인 방법.
실시양태 92. 질환 또는 병태의 치료를 필요로 하는 대상체에서 이를 치료하는 방법으로서, 안티센스 올리고머를 포함하는 조성물을 대상체에게 투여하는 단계를 포함하고, 안티센스 올리고머는 SCN1A의 인트론 20에 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 적어도 8개의 인접한 뉴클레오티드의 서열을 포함하는 것인 방법.
실시양태 93. 질환 또는 병태의 치료를 필요로 하는 대상체에서 이를 치료하는 방법으로서, 안티센스 올리고머를 포함하는 조성물을 대상체에게 투여하는 단계를 포함하고, 안티센스 올리고머는 서열 번호 7 내지 10 중 어느 하나에 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 적어도 8개의 인접한 뉴클레오티드의 서열을 포함하는 것인 방법.
실시양태 94. 실시양태 78 내지 93 중 어느 하나에 있어서, 넌센스 매개 RNA 붕괴 유도 엑손은 표적 단백질 또는 기능성 RNA를 코딩하는 NMD 엑손 mRNA로부터 스플라이싱되는 것인 방법.
실시양태 95. 실시양태 78 내지 94 중 어느 하나에 있어서, 표적 단백질은 넌센스 매개 RNA 붕괴 유도 엑손에 의해 코딩되는 아미노산 서열을 포함하지 않는 것인 방법.
실시양태 96. 실시양태 78 내지 95 중 어느 하나에 있어서, 표적 단백질은 전장 표적 단백질인 방법.
실시양태 97. 실시양태 78 내지 96 중 어느 하나에 있어서, 작용제는 NMD 엑손 mRNA의 표적화된 부분에 상보적인 안티센스 올리고머(ASO)인 방법.
실시양태 98. 실시양태 78 내지 97 중 어느 하나에 있어서, mRNA는 프리-mRNA인 방법.
실시양태 99. 실시양태 78 내지 98 중 어느 하나에 있어서, 접촉 단계는 치료제를 세포의 핵에 있는 mRNA에 접촉시키는 것을 포함하는 것인 방법.
실시양태 100. 실시양태 78 내지 99 중 어느 하나에 있어서, 표적 단백질 또는 기능성 RNA는 대상체에서 표적 단백질 또는 기능성 RNA의 결핍을 교정하는 것인 방법.
실시양태 101. 실시양태 78 내지 100 중 어느 하나에 있어서, 세포는 SCN1A 단백질의 결핍된 양 또는 활성에 의해 야기되는 병태를 갖는 대상체에 있거나 그로부터 유래하는 것인 방법.
실시양태 102. 실시양태 78 내지 101 중 어느 하나에 있어서, 표적 단백질의 결핍된 양은 표적 단백질의 반가불충분성에 의해 야기되고, 대상체는 기능성 표적 단백질을 코딩하는 제1 대립 유전자, 및 표적 단백질이 생성되지 않거나 감소한 수준으로 생성되는 제2 대립 유전자, 또는 비기능성 또는 부분 기능성 표적 단백질을 코딩하는 제2 대립 유전자를 가지며, 안티센스 올리고머는 제1 대립 유전자로부터 전사된 NMD 엑손 mRNA의 표적화된 부분에 결합하는 것인 방법.
실시양태 103. 실시양태 78 내지 101 중 어느 하나에 있어서, 대상체는 표적 단백질의 양 또는 기능의 결핍으로 인한 장애에 의해 야기되는 병태를 가지며, 대상체는
(a) (i) 표적 단백질이 야생형 대립 유전자로부터의 생산과 비교하여 감소한 수준으로 생성되거나,
(ii) 표적 단백질이 동등한 야생형 단백질과 비교하여 기능이 감소한 형태로 생성되거나,
(iii) 표적 단백질이 생성되지 않는
제1 돌연변이 대립 유전자; 및
(b) (i) 표적 단백질이 야생형 대립 유전자로부터의 생산과 비교하여 감소한 수준으로 생성되거나,
(ii) 표적 단백질이 동등한 야생형 단백질과 비교하여 기능이 감소한 형태로 생성되거나,
(iii) 표적 단백질이 생성되지 않는
제2 돌연변이 대립 유전자를 가지며,
대상체가 제1 돌연변이 대립 유전자 (a)(iii)을 가질 때, 제2 돌연변이 대립 유전자는 (b)(i) 또는 (b)(ii)이고, 대상체가 제2 돌연변이 대립 유전자 (b)(iii)을 가질 때, 제1 돌연변이 대립 유전자는 (a)(i) 또는 (a)(ii)이며, NMD 엑손 mRNA는 (a)(i) 또는 (a)(ii)인 제1 돌연변이 대립 유전자 및/또는 (b)(i) 또는 (b)(ii) 인 제2 대립 유전자로부터 전사되는 것인 방법.
실시양태 104. 실시양태 103에 있어서, 표적 단백질은 동등한 야생형 단백질과 비교하여 기능이 감소한 형태로 생성되는 것인 방법.
실시양태 105. 실시양태 103에 있어서, 표적 단백질은 동등한 야생형 단백질과 비교하여 완전히 기능적인 형태로 생성되는 것인 방법.
실시양태 106. 실시양태 78 내지 105 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 넌센스 매개 RNA 붕괴 유도 엑손 내에 있는 것인 방법.
실시양태 107. 실시양태 78 내지 105 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 넌센스 매개 RNA 붕괴 유도 엑손의 상류 또는 하류에 있는 것인 방법.
실시양태 108. 실시양태 78 내지 107 중 어느 하나에 있어서, NMD 엑손 mRNA는 서열 번호 2, 7 내지 10, 12, 및 17 내지 20 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함하는 것인 방법.
실시양태 109. 실시양태 78 내지 107 중 어느 하나에 있어서, NMD 엑손 mRNA는 서열 번호 1, 3 내지 6, 11, 및 13 내지 16과 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 유전자 서열에 의해 코딩되는 것인 방법.
실시양태 110. 실시양태 78 내지 107 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 서열 번호 2, 7 내지 10, 12, 및 17 내지 20의 적어도 8개의 인접한 핵산을 포함하는 영역과 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함하는 것인 방법.
실시양태 111. 실시양태 78 내지 110 중 어느 하나에 있어서, 작용제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21 내지 114 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 112. 실시양태 78 내지 105 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x 내에 있는 것인 방법.
실시양태 113. 실시양태 112에 있어서, 작용제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 42 내지 50, 또는 231 내지 239 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 114. 실시양태 78 내지 105 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x의 상류 또는 하류에 있는 것인 방법.
실시양태 115. 실시양태 114에 있어서, 작용제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21 내지 38, 53 내지 67, 210 내지 227, 또는 242 내지 256 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 116. 실시양태 78 내지 105 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 엑손 20x의 엑손-인트론 접합부를 포함하는 것인 방법.
실시양태 117. 실시양태 116에 있어서, 작용제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 39 내지 41, 51, 52, 228 내지 230, 240, 또는 241 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 118. 실시양태 78 내지 105 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 Scn1a의 넌센스 매개 RNA 붕괴 유도 엑손 21x 내에 있는 것인 방법.
실시양태 119. 실시양태 118에 있어서, 작용제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 89 내지 97 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 120. 실시양태 78 내지 105 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 Scn1a의 넌센스 매개 RNA 붕괴 유도 엑손 21x의 상류 또는 하류에 있는 것인 방법.
실시양태 121. 실시양태 120에 있어서, 작용제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 68 내지 85 및 100 내지 114 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 122. 실시양태 78 내지 105 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 Scn1a의 엑손 21x의 엑손-인트론 접합부를 포함하는 것인 방법.
실시양태 123. 실시양태 122에 있어서, 작용제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 86 내지 88 및 98 내지 99 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 124. 실시양태 78 내지 123 중 어느 하나에 있어서, 생성된 표적 단백질은 전장 단백질, 또는 야생형 단백질인 방법.
실시양태 125. 실시양태 78 내지 124 중 어느 하나에 있어서, 안티센스 올리고머와 접촉된 세포에서 생성된 표적 단백질 또는 기능성 RNA를 코딩하는 가공된 mRNA의 총량은 대조군 세포에서 생성된 표적 단백질 또는 기능성 RNA를 코딩하는 가공된 mRNA의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가하는 것인 방법.
실시양태 126. 실시양태 78 내지 124 중 어느 하나에 있어서, 안티센스 올리고머와 접촉된 세포에 의해 생성된 표적 단백질의 총량은 대조군 세포에 의해 생성된 표적 단백질의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가하는 것인 방법.
실시양태 127. 실시양태 78 내지 126 중 어느 하나에 있어서, 작용제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로티오에이트 결합 또는 포스포로디아미데이트 결합을 포함하는 백본 변형을 포함하는 것인 방법.
실시양태 128. 실시양태 78 내지 127 중 어느 하나에 있어서, 작용제는 안티센스 올리고머(ASO)이고, 안티센스 올리고머는 포스포로디아미데이트 모르폴리노, 잠금 핵산, 펩티드 핵산, 2'-O-메틸, 2'-플루오로, 또는 2'-O-메톡시에틸 모이어티를 포함하는 것인 방법.
실시양태 129. 실시양태 78 내지 128 중 어느 하나에 있어서, 작용제는 안티센스 올리고머(ASO)이고, 안티센스 올리고머는 하나 이상의 변형된 당 모이어티를 포함하는 것인 방법.
실시양태 130. 실시양태 129에 있어서, 각각의 당 모이어티는 변형된 당 모이어티인 방법.
실시양태 131. 실시양태 78 내지 130 중 어느 하나에 있어서, 작용제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 8 내지 50개의 핵염기, 8 내지 40개의 핵염기, 8 내지 35개의 핵염기, 8 내지 30개의 핵염기, 8 내지 25개의 핵염기, 8 내지 20개의 핵염기, 8 내지 15개의 핵염기, 9 내지 50개의 핵염기, 9 내지 40개의 핵염기, 9 내지 35개의 핵염기, 9 내지 30개의 핵염기, 9 내지 25개의 핵염기, 9 내지 20개의 핵염기, 9 내지 15개의 핵염기, 10 내지 50개의 핵염기, 10 내지 40개의 핵염기, 10 내지 35개의 핵염기, 10 내지 30개의 핵염기, 10 내지 25개의 핵염기, 10 내지 20개의 핵염기, 10 내지 15개의 핵염기, 11 내지 50개의 핵염기, 11 내지 40개의 핵염기, 11 내지 35개의 핵염기, 11 내지 30개의 핵염기, 11 내지 25개의 핵염기, 11 내지 20개의 핵염기, 11 내지 15개의 핵염기, 12 내지 50개의 핵염기, 12 내지 40개의 핵염기, 12 내지 35개의 핵염기, 12 내지 30개의 핵염기, 12 내지 25개의 핵염기, 12 내지 20개의 핵염기, 또는 12 내지 15개의 핵염기로 이루어지는 것인 방법.
실시양태 132. 실시양태 78 내지 131 중 어느 하나에 있어서, 작용제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 단백질을 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 98%, 적어도 99%, 또는 100% 상보적인 것인 방법.
실시양태 133. 실시양태 78 내지 132 중 어느 하나에 있어서, SCN1A mRNA 또는 단백질 발현을 평가하는 단계를 추가로 포함하는 방법.
실시양태 134. 실시양태 1 내지 133 중 어느 하나에 있어서, 드라벳 증후군; 열성 발작 플러스를 동반하는 전신 뇌전증 2형; 가족성 열성 발작 3A; 가족성 편마비 편두통 3; 자폐증; 조기 유아 간질성 뇌병증 13; 동기능 부전 증후군 1; 알츠하이머병 또는 뇌전증에서의 돌연사(SUDEP)가 치료되고 안티센스 올리고머는 SCN1A NMD 엑손 mRNA의 표적화된 부분에 결합하며, 표적화된 부분은 서열 번호 7 내지 10 및 17 내지 20으로부터 선택된 서열 내에 있는 것인 방법.
실시양태 135. 실시양태 78 내지 134 중 어느 하나에 있어서, 대상체는 인간인 방법.
실시양태 136. 실시양태 78 내지 135 중 어느 하나에 있어서, 대상체는 비인간 동물인 방법.
실시양태 137. 실시양태 78 내지 136 중 어느 하나에 있어서, 대상체는 태아, 배아, 또는 소아인 방법.
실시양태 138. 실시양태 78 내지 137 중 어느 하나에 있어서, 세포는 생체 외 세포인 방법.
실시양태 139. 실시양태 78 내지 138 중 어느 하나에 있어서, 치료제는 대상체의 수막공간내 주사, 뇌실내 주사, 복강내 주사, 근육내 주사, 피하 주사, 안내 주사, 또는 정맥내 주사에 의해 투여되는 것인 방법.
실시양태 140. 실시양태 78 내지 139 중 어느 하나에 있어서, 제2 치료제를 대상체에게 투여하는 단계를 추가로 포함하는 방법.
실시양태 141. 실시양태 140에 있어서, 제2 치료제는 소분자인 방법.
실시양태 142. 실시양태 140에 있어서, 제2 치료제는 ASO인 방법.
실시양태 143. 실시양태 142에 있어서, ASO는 서열 번호 115 내지 161 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
실시양태 144. 실시양태 140 내지 142 중 어느 하나에 있어서, 제2 치료제는 인트론 유지를 교정하는 것인 방법.
실시양태 145. 실시양태 78 내지 144 중 어느 하나의 방법에 사용되는 안티센스 올리고머.
실시양태 146. 서열 번호 21 내지 114 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함하는 안티센스 올리고머.
실시양태 147. 실시양태 145 또는 146의 안티센스 올리고머 및 부형제를 포함하는 약학 조성물.
실시양태 148. 치료를 필요로 하는 대상체를 치료하는 방법으로서, 실시양태 147의 약학 조성물을 대상체에게 투여하는 단계를 포함하며, 투여 단계는 수막공간내 주사, 뇌실내 주사, 복강내 주사, 근육내 주사, 피하 주사, 안내 주사, 또는 정맥내 주사에 의한 것인 방법.
실시 형태 149. 결핍된 단백질 또는 결핍된 기능성 RNA와 관련된 질환 또는 병태의 치료를 필요로 하는 대상체에서 이를 치료하기 위해 세포에 의한 표적 단백질 또는 기능성 RNA의 발현을 증가시키는 방법에 사용하기 위한 치료제를 포함하는 조성물로서, 결핍된 단백질 또는 결핍된 기능성 RNA는 대상체에서 양 또는 활성이 결핍되고, 표적 단백질은
(a) 결핍된 단백질; 또는
(b) 대상체에서 결핍된 단백질을 기능적으로 증대시키거나 대체하는 보상 단백질이고;
기능성 RNA는
(c) 결핍된 RNA; 또는
(d) 대상체에서 결핍된 기능성 RNA를 기능적으로 증대시키거나 대체하는 보상 기능성 RNA이고;
치료제는 표적 단백질 또는 기능성 RNA를 코딩하는 NMD 엑손 mRNA로부터의 넌센스 매개 RNA 붕괴 유도 엑손의 배제를 향상시킴으로써, 대상체에서 표적 단백질 또는 기능성 RNA의 생산 또는 활성을 증가시키는 것인 조성물.
실시양태 150. 질환 또는 병태의 치료를 필요로 하는 대상체에서 이를 치료하는 방법에 사용하기 위한 치료제를 포함하는 조성물로서, 방법은 대상체의 세포에 의한 SCN1A 단백질의 발현을 조절하는 단계를 포함하고, 세포는 넌센스 매개 RNA 붕괴 유도 엑손을 함유하고(NMD 엑손 mRNA) SCN1A 단백질을 코딩하는 mRNA를 가지며, 방법은 세포를 치료제와 접촉시키는 단계를 포함하고, 그로 인하여 SCN1A 단백질을 코딩하는 NMD 엑손 mRNA로부터 넌센스 매개 RNA 붕괴 유도 엑손의 배제가 조절되고, 이로써 대상체의 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 조절하고, SCN1A 단백질의 발현을 조절하는 것인 조성물.
실시양태 151. 실시양태 150에 있어서, 질환 또는 병태는 드라벳 증후군(DS); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 동기능 부전 증후군 1; 자폐증; 또는 가족성 편마비 편두통 3; 및 알츠하이머병으로 이루어진 군으로부터 선택되는 것인 조성물.
실시양태 152. 실시양태 150 또는 151에 있어서, SCN1A 단백질 및 NMD 엑손 mRNA는 SCN1A 유전자에 의해 코딩되는 것인 조성물.
실시양태 153. 실시양태 149 내지 152 중 어느 하나에 있어서, 넌센스 매개 RNA 붕괴 유도 엑손은 SCN1A 단백질을 코딩하는 NMD 엑손 mRNA로부터 스플라이싱되는 것인 조성물.
실시양태 154. 실시양태 149 내지 153 중 어느 하나에 있어서, SCN1A 단백질은 넌센스 매개 RNA 붕괴 유도 엑손에 의해 코딩되는 아미노산 서열을 포함하지 않는 것인 조성물.
실시양태 155. 실시양태 149 내지 154 중 어느 하나에 있어서, SCN1A 단백질은 전장 SCN1A 단백질인 조성물.
실시양태 156. 실시양태 149 내지 155 중 어느 하나에 있어서, 치료제는 NMD 엑손 mRNA의 표적화된 부분에 상보적인 안티센스 올리고머(ASO)인 조성물.
실시양태 157. 실시양태 149 내지 156 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 넌센스 매개 RNA 붕괴 유도 엑손 내에 있는 NMD 엑손 mRNA의 일부를 표적화하는 것인 조성물.
실시양태 158. 실시양태 149 내지 156 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 넌센스 매개 RNA 붕괴 유도 엑손의 상류 또는 하류에 있는 NMD 엑손 mRNA의 일부를 표적화하는 것인 조성물.
실시양태 159. 실시양태 149 내지 158 중 어느 하나에 있어서, 표적 단백질은 SCN1A인 조성물.
실시양태 160. 실시양태 159에 있어서, NMD 엑손 mRNA는 서열 번호 2, 7 내지 10, 12, 및 17 내지 20 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함하는 것인 조성물.
실시양태 161. 실시양태 159에 있어서, NMD 엑손 mRNA는 서열 번호 1, 3 내지 6, 11, 및 13 내지 16과 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 유전자 서열에 의해 코딩되는 것인 조성물.
실시양태 162. 실시양태 159에 있어서, NMD 엑손 mRNA의 표적화된 부분은 서열 번호 2, 7 내지 10, 12, 및 17 내지 20의 적어도 8개의 인접한 핵산을 포함하는 영역과 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함하는 것인 조성물.
실시양태 163. 실시양태 159 내지 162 중 어느 하나에 있어서, NMD 엑손 mRNA의 표적화된 부분은 (i) 넌센스 매개 RNA 붕괴 유도 엑손 20x 내에 있거나, (ii) 넌센스 매개 RNA 붕괴 유도 엑손 20x의 상류 또는 하류에 있거나, (iii) 넌센스 매개 RNA 붕괴 유도 엑손 20x의 엑손-인트론 접합부를 포함하는 것인 조성물.
실시양태 164. 실시양태 159 내지 163 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21 내지 114 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 조성물
실시양태 165. 실시양태 149 내지 164 중 어느 하나에 있어서, 질환 또는 병태는 Nav1.1의 기능 상실 돌연변이에 의해 유발되는 것인 조성물.
실시양태 166. 실시양태 149 내지 165 중 어느 하나에 있어서, 질환 또는 병태는 SCN1A 유전자의 반가불충분성과 관련되며, 대상체는 기능성 SCN1A를 코딩하는 제1 대립 유전자, 및 SCN1A가 생성되지 않거나 감소한 수준으로 생성되는 제2 대립 유전자, 또는 비기능성 SCN1A 또는 부분 기능성 SCN1A를 코딩하는 제2 대립 유전자를 갖는 것인 조성물.
실시양태 167. 실시양태 149 내지 166 중 어느 하나에 있어서, 질환 또는 병태는, 경우에 따라 Nav1.1의 기능 상실 돌연변이에 의해 유발되는, 뇌병증인 조성물.
실시양태 168. 실시양태 167에 있어서, 뇌병증은 간질성 뇌병증인 조성물.
실시양태 169. 실시양태 165 또는 166에 있어서, 질환 또는 병태는 드라벳 증후군(DS); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 동기능 부전 증후군 1; 자폐증; 또는 유아기의 악성 이동 부분 발작인 조성물.
실시양태 170. 실시양태 168에 있어서, GEFS+는 열성 발작 플러스를 동반하는 전신 뇌전증 2형인 조성물.
실시양태 171. 실시양태 168에 있어서, 열성 발작은 가족성 열성 발작 3A인 조성물.
실시양태 172. 실시양태 168에 있어서, SMEB는 전신 극파가 없는 SMEB(SMEB-SW), 근간대성 발작이 없는 SMEB(SMEB-M), SMEI의 하나 초과의 특징이 결여된 SMEB(SMEB-O), 또는 전신 강직성 간대 발작을 동반한 난치성 소아기 뇌전증(ICEGTC)인 조성물.
실시양태 173. 실시양태 165 내지 172 중 어느 하나에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 촉진하고 SCN1A의 발현을 증가시키는 것인 조성물.
실시양태 174. 실시양태 165 내지 173 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 22 내지 24, 26, 27, 29 내지 35, 37 내지 62, 또는 64 내지 67 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함하는 것인 조성물.
실시양태 175. 실시양태 149 내지 164 중 어느 하나에 있어서, 질환 또는 병태는 Nav1.1의 기능 획득 돌연변이에 의해 유발되는 것인 조성물.
실시 형태 176. 실시 형태 149 내지 164 또는 175 중 어느 하나에 있어서, 대상체는 세포에서 SCN1A가 증가한 수준으로 생성되는 대립 유전자, 또는 Nav1.1의 증가한 활성을 유도하는 돌연변이 SCN1A를 코딩하는 대립 유전자를 갖는 것인 조성물.
실시양태 177. 실시양태 149 내지 164, 175, 또는 176 중 어느 하나에 있어서, 질환 또는 병태는 편두통인 조성물.
실시양태 178. 실시양태 177에 있어서, 편두통은 가족성 편마비 편두통 3인 조성물.
실시양태 179. 실시양태 149 내지 164, 175, 또는 176 중 어느 하나에 있어서, 질환 또는 병태는 Nav1.1 유전성 뇌전증인 조성물.
실시양태 180. 실시양태 149 내지 164, 또는 175 내지 179 중 어느 하나에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 억제하고 SCN1A의 발현을 감소시키는 것인 조성물.
실시양태 181. 실시양태 149 내지 164, 또는 175 내지 180 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21, 25, 28, 36, 또는 63 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함하는 것인 조성물.
실시양태 182. 실시양태 149 내지 181 중 어느 하나에 있어서, 표적 단백질 또는 기능성 RNA를 코딩하는 가공된 mRNA는 전장의 성숙한 mRNA, 또는 야생형의 성숙한 mRNA인 조성물.
실시양태 183. 실시양태 149 내지 182 중 어느 하나에 있어서, 생성된 표적 단백질은 전장 단백질, 또는 야생형 단백질인 조성물.
실시양태 184. 실시양태 149 내지 183 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로티오에이트 결합 또는 포스포로디아미데이트 결합을 포함하는 백본 변형을 포함하는 것인 조성물.
실시양태 185. 실시양태 149 내지 184 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 안티센스 올리고뉴클레오티드인 조성물.
실시양태 186. 실시양태 149 내지 185 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로디아미데이트 모르폴리노, 잠금 핵산, 펩티드 핵산, 2'-O-메틸, 2'-플루오로, 또는 2'-O-메톡시에틸 모이어티를 포함하는 것인 조성물.
실시양태 187. 실시양태 149 내지 186 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 하나 이상의 변형된 당 모이어티를 포함하는 것인 조성물.
실시양태 188. 실시양태 187에 있어서, 각각의 당 모이어티는 변형된 당 모이어티인 조성물.
실시양태 189. 실시양태 149 내지 188 중 어느 하나에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 8 내지 50개의 핵염기, 8 내지 40개의 핵염기, 8 내지 35개의 핵염기, 8 내지 30개의 핵염기, 8 내지 25개의 핵염기, 8 내지 20개의 핵염기, 8 내지 15개의 핵염기, 9 내지 50개의 핵염기, 9 내지 40개의 핵염기, 9 내지 35개의 핵염기, 9 내지 30개의 핵염기, 9 내지 25개의 핵염기, 9 내지 20개의 핵염기, 9 내지 15개의 핵염기, 10 내지 50개의 핵염기, 10 내지 40개의 핵염기, 10 내지 35개의 핵염기, 10 내지 30개의 핵염기, 10 내지 25개의 핵염기, 10 내지 20개의 핵염기, 10 내지 15개의 핵염기, 11 내지 50개의 핵염기, 11 내지 40개의 핵염기, 11 내지 35개의 핵염기, 11 내지 30개의 핵염기, 11 내지 25개의 핵염기, 11 내지 20개의 핵염기, 11 내지 15개의 핵염기, 12 내지 50개의 핵염기, 12 내지 40개의 핵염기, 12 내지 35개의 핵염기, 12 내지 30개의 핵염기, 12 내지 25개의 핵염기, 12 내지 20개의 핵염기, 또는 12 내지 15개의 핵염기로 이루어지는 것인 조성물.
실시양태 190. 안티센스 올리고머를 포함하는 조성물로서, 안티센스 올리고머는 SCN1A의 인트론 20에 상보적인 적어도 80%, 85%, 90%, 95%, 97% 또는 100% 상보적인 적어도 8개의 인접한 뉴클레오티드의 서열을 포함하는 것인 조성물.
실시 형태 191. 안티센스 올리고머를 포함하는 조성물로서, 안티센스 올리고머는 서열 번호 7 내지 10 중 어느 하나와 적어도 80%, 85%, 90%, 95%, 97% 또는 100% 상보적인 적어도 8개의 인접한 뉴클레오티드의 서열을 포함하는 것인 조성물.
실시양태 192. 실시양태 149 내지 191 중 어느 하나의 조성물의 치료제 및 부형제를 포함하는 약학 조성물.
실시양태 193. 치료를 필요로 하는 대상체를 치료하는 방법으로서, 실시양태 192의 약학 조성물을 대상체에게 투여하는 단계를 포함하며, 투여 단계는 수막공간내 주사, 뇌실내 주사, 복강내 주사, 근육내 주사, 피하 주사, 안내 주사, 또는 정맥내 주사에 의한 것인 약학 조성물.
실시양태 194. SCN1A mRNA 전사체의 표적 서열에 혼성화하는 안티센스 올리고머 및 약학적으로 허용 가능한 부형제를 포함하는 약학 조성물로서, SCN1A mRNA 전사체는 넌센스 매개 RNA 붕괴 유도 엑손을 포함하며, 안티센스 올리고머는 SCN1A mRNA 전사체로부터의 넌센스 매개 RNA 붕괴 유도 엑손의 배제를 유도하는 것인 약학 조성물.
실시양태 195. 실시양태 194에 있어서, SCN1A mRNA 전사체는 SCN1A NMD 엑손 mRNA 전사체인 약학 조성물.
실시양태 196. 실시양태 194 또는 195에 있어서, SCN1A NMD 엑손 mRNA 전사체의 표적화된 부분은 (i) 넌센스 매개 RNA 붕괴 유도 엑손 20x 내에 있거나, (ii) 넌센스 매개 RNA 붕괴 유도 엑손 20x의 상류 또는 하류에 있거나, (iii) 넌센스 매개 RNA 붕괴 유도 엑손 20x의 엑손-인트론 접합부를 포함하는 것인 약학 조성물.
실시양태 197. 실시양태 194 또는 196에 있어서, SCN1A NMD 엑손 mRNA 전사체는 서열 번호 1, 3 내지 6, 11, 및 13 내지 16 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 서열 동일성을 갖는 유전자 서열에 의해 코딩되는 것인 약학 조성물.
실시양태 198. 실시양태 194 또는 196에 있어서, SCN1A NMD 엑손 mRNA 전사체는 서열 번호 2, 7 내지 10, 12, 및 17 내지 20 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% 또는 100% 서열 동일성을 갖는 서열을 포함하는 것인 약학 조성물.
실시양태 199. 실시양태 194에 있어서, 안티센스 올리고머는 포스포로티오에이트 결합 또는 포스포로디아미데이트 결합을 포함하는 백본 변형을 포함하는 것인 약학 조성물.
실시양태 200. 실시양태 194에 있어서, 안티센스 올리고머는 안티센스 올리고뉴클레오티드인 약학 조성물.
실시양태 201. 실시양태 194에 있어서, 안티센스 올리고머는 포스포로디아미데이트 모르폴리노, 잠금 핵산, 펩티드 핵산, 2'-O-메틸, 2'-플루오로, 또는 2'-O-메톡시에틸 모이어티를 포함하는 것인 약학 조성물.
실시양태 202. 실시양태 194에 있어서, 안티센스 올리고머는 하나 이상의 변형된 당 모이어티를 포함하는 것인 약학 조성물.
실시양태 203. 실시양태 194에 있어서, 안티센스 올리고머는 8 내지 50개의 핵염기, 8 내지 40개의 핵염기, 8 내지 35개의 핵염기, 8 내지 30개의 핵염기, 8 내지 25개의 핵염기, 8 내지 20개의 핵염기, 8 내지 15개의 핵염기, 9 내지 50개의 핵염기, 9 내지 40개의 핵염기, 9 내지 35개의 핵염기, 9 내지 30개의 핵염기, 9 내지 25개의 핵염기, 9 내지 20개의 핵염기, 9 내지 15개의 핵염기, 10 내지 50개의 핵염기, 10 내지 40개의 핵염기, 10 내지 35개의 핵염기, 10 내지 30개의 핵염기, 10 내지 25개의 핵염기, 10 내지 20개의 핵염기, 10 내지 15개의 핵염기, 11 내지 50개의 핵염기, 11 내지 40개의 핵염기, 11 내지 35개의 핵염기, 11 내지 30개의 핵염기, 11 내지 25개의 핵염기, 11 내지 20개의 핵염기, 11 내지 15개의 핵염기, 12 내지 50개의 핵염기, 12 내지 40개의 핵염기, 12 내지 35개의 핵염기, 12 내지 30개의 핵염기, 12 내지 25개의 핵염기, 12 내지 20개의 핵염기, 또는 12 내지 15개의 핵염기를 포함하는 것인 약학 조성물.
실시양태 204. 실시양태 194 또는 195에 있어서, 안티센스 올리고머는 SCN1A NMD 엑손 mRNA 전사체의 표적화된 부분에 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 98%, 적어도 99%, 또는 100% 상보적인 것인 약학 조성물.
실시양태 205. 실시양태 194 또는 195에 있어서, SCN1A NMD 엑손 mRNA 전사체의 표적화된 부분은 서열 번호 2, 7 내지 10, 12, 및 17 내지 20으로부터 선택된 서열 내에 있는 것인 약학 조성물.
실시양태 206. 실시양태 194에 있어서, 안티센스 올리고머는 서열 번호 21 내지 114 중 어느 하나와 적어도 약 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 또는 99% 서열 동일성인 뉴클레오티드 서열을 포함하는 것인 약학 조성물.
실시양태 207. 실시양태 194에 있어서, 안티센스 올리고머는 서열 번호 21 내지 114로부터 선택된 뉴클레오티드 서열을 포함하는 것인 약학 조성물.
실시양태 208. 실시양태 194 내지 실시양태 207 중 어느 하나에 있어서, 수막공간내 주사, 뇌실내 주사, 복강내 주사, 근육내 주사, 피하 주사, 안내 주사, 또는 정맥내 주사를 위해 제제화되는 약학 조성물.
실시양태 209. 넌센스 매개 RNA 붕괴 유도 엑손의 제거를 촉진하게 하여 기능적 형태의 SCN1A 단백질을 코딩하는 완전히 가공된 SCN1A mRNA 전사체를 생성하기 위해 결핍된 SCN1A mRNA 전사체의 가공을 유도하는 방법으로서,
(a) 안티센스 올리고머를 대상체의 표적 세포에 접촉시키는 단계;
(b) 안티센스 올리고머를 결핍된 SCN1A mRNA 전사체에 혼성화시키는 단계로서, 결핍된 SCN1A mRNA 전사체는 기능적 형태의 SCN1A 단백질을 코딩할 수 있고 하나 이상의 넌센스 매개 RNA 붕괴 유도 엑손을 포함하는 것인 단계;
(c) 기능적 형태의 SCN1A 단백질을 코딩하는 완전히 가공된 SCN1A mRNA 전사체를 생성하기 위해 결핍된 SCN1A mRNA 전사체로부터 하나 이상의 넌센스 매개 RNA 붕괴 유도 엑손을 제거하는 단계; 및
(d) 완전히 가공된 SCN1A mRNA 전사체로부터 기능적 형태의 SCN1A 단백질을 번역하는 단계
를 포함하는 방법.
실시양태 210. SCN1A 단백질의 결핍된 양 또는 활성에 의해 야기되는 병태를 갖는 대상체를 치료하는 방법으로서, 서열 번호 24 내지 114 중 어느 하나와 적어도 약 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 또는 99% 서열 동일성을 갖는 뉴클레오티드 서열을 포함하는 안티센스 올리고머를 대상체에게 투여하는 단계를 포함하는 방법.
실시양태 211. 세포에 의한 표적 단백질 또는 기능성 RNA의 유전자 발현을 증가시키는 작용제를 스크리닝하는 방법으로서, 세포는 넌센스 매개 RNA 붕괴 유도 엑손을 함유하는 mRNA(NMD 엑손 mRNA)를 가지며, NMD 엑손 mRNA는 표적 단백질 또는 기능성 RNA를 코딩하고,
(a) NMD 엑손 mRNA를 표적화하는 시험 작용제를 제1 세포에 접촉시키는 단계;
(b) 대조 작용제를 제2 세포에 접촉시키는 단계;
(c) 제1 세포에서 제1 수준을 결정하는 단계로서, 제1 수준은 (i) RNA 붕괴유도 엑손을 포함하지 않는 NMD 엑손 mRNA에 의해 코딩된 RNA 전사체, 또는 (ii) RNA 붕괴 유도 엑손에 의해 코딩되는 아미노산 서열을 포함하지 않는 NMD 엑손 mRNA에 의해 코딩된 단백질의 수준인 단계;
(d) 제2 세포에서 제2 수준을 결정하는 단계로서, 제2 수준은 (i) RNA 붕괴 유도 엑손을 포함하지 않는 NMD 엑손 mRNA에 의해 코딩된 RNA 전사체, 또는 (ii) RNA 붕괴 유도 엑손에 의해 코딩되는 아미노산 서열을 포함하지 않는 NMD 엑손 mRNA에 의해 코딩된 단백질의 수준인 단계;
제1 수준이 제2 수준보다 높은 경우;
(e) 시험 작용제를 선택하는 단계
를 포함하는 방법.
실시양태 212. 세포에 의한 표적 단백질 또는 기능성 RNA의 유전자 발현을 증가시키는 작용제를 스크리닝하는 방법으로서, 세포는 넌센스 매개 RNA 붕괴 유도 엑손을 함유하는 mRNA(NMD 엑손 mRNA)를 가지며, NMD 엑손 mRNA는 표적 단백질 또는 기능성 RNA를 코딩하고,
(a) NMD 엑손 mRNA를 표적화하는 시험 작용제를 제1 세포에 접촉시키는 단계;
(b) 대조 작용제를 제2 세포에 접촉시키는 단계;
(c) 제1 세포에서 제1 수준을 결정하는 단계로서, 제1 수준은 (i) RNA 붕괴유도 엑손을 포함하는 NMD 엑손 mRNA에 의해 코딩된 RNA 전사체, 또는 (ii) RNA 붕괴 유도 엑손에 의해 코딩되는 아미노산 서열을 포함하는 NMD 엑손 mRNA에 의해 코딩된 단백질의 수준인 단계;
(d) 제2 세포에서 제2 수준을 결정하는 단계로서, 제2 수준은 (i) RNA 붕괴 유도 엑손을 포함하는 NMD 엑손 mRNA에 의해 코딩된 RNA 전사체, 또는 (ii) RNA 붕괴 유도 엑손에 의해 코딩되는 아미노산 서열을 포함하는 NMD 엑손 mRNA에 의해 코딩된 단백질의 수준인 단계;
제1 수준이 제2 수준보다 낮은 경우;
(e) 시험 작용제를 선택하는 단계
를 포함하는 방법.
실시양태 213. 실시양태 211 또는 212에 있어서, 단백질 합성 억제제를 제1 세포 및 제2 세포에 접촉시키는 단계를 포함하고; 제1 수준은 RNA 붕괴 유도 엑손을 포함하는 NMD 엑손 mRNA에 의해 코딩된 RNA 전사체의 수준이고; 제2 수준은 RNA 붕괴 유도 엑손을 포함하는 NMD 엑손 mRNA에 의해 코딩된 RNA 전사체의 수준인 방법.
실시양태 214. 드라벳 증후군(DS), 열성 발작 플러스를 동반하는 전신 뇌전증 2형; 가족성 열성 발작 3A; 가족성 편마비 편두통 3; 자폐증; 조기 유아 간질성 뇌병증 13; 동기능 부전 증후군 1; 알츠하이머병 또는 SUDEP (뇌전증에서의 돌연사)의 치료를 필요로 하는 대상체의 세포에 의한 표적 단백질 또는 기능성 RNA의 발현을 증가시킴으로써 대상체에서 이를 치료하는 방법으로서, 세포는 넌센스 매개 RNA 붕괴 유도 엑손를 함유하는 mRNA(NMD 엑손 mRNA)를 가지며, NMD 엑손 mRNA는 표적 단백질 또는 기능성 RNA를 코딩하고, 표적 단백질 또는 기능성 RNA를 코딩하는 NMD 엑손 mRNA의 스플라이싱을 조절하는 치료제와 대상체의 세포를 접촉시킴으로써, 넌센스 매개 RNA 붕괴 유도 엑손이 표적 단백질 또는 기능성 RNA를 코딩하는 NMD 엑손 mRNA로부터 배제되어, 이로써 대상체의 세포에서 표적 단백질 또는 기능성 RNA를 코딩하는 가공된 mRNA의 수준을 증가시키고, 표적 단백질 또는 기능성 RNA의 발현을 증가시키는 단계
를 포함하는 방법.
실시양태 215. 넌센스 매개 RNA 붕괴 유도 엑손을 함유하고(NMD 엑손 mRNA) SCN1A 단백질을 코딩하는 mRNA를 갖는 세포에 의한 SCN1A 단백질의 발현을 증가시키는 방법으로서, 세포를 SCN1A 단백질을 코딩하는 NMD 엑손 mRNA의 스플라이싱을 조절하는 작용제에 접촉시킴으로써, 넌센스 매개 RNA 붕괴 유도 엑손이 SCN1A 단백질을 코딩하는 NMD 엑손 mRNA로부터 배제되어, 이로써 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 증가시키고, SCN1A 단백질의 발현을 증가시키는 단계를 포함하는 방법.
실시양태 216. 실시양태 214 또는 215에 있어서, 작용제는
(a) 표적 단백질 또는 기능성 RNA를 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 결합하거나;
(b) 스플라이스좀의 하나 이상의 성분에 결합하거나;
(c) (a)와 (b)의 조합인 방법.
본 발명의 바람직한 실시양태가 여기에 제시되고 설명되었지만, 이러한 실시양태는 단지 예로서 제공된다는 것은 당업자에게 명백할 것이다. 당업자는 본 발명을 벗어나지 않으면서 다수의 변형, 변경 및 치환을 생각해 낼 것이다. 본원에 기술된 본 발명의 실시양태에 대한 다양한 대안이 본 발명을 실시하는 데 사용될 수 있음을 이해해야 한다. 다음의 청구 범위는 본 발명의 범위를 정의하고 이들 청구 범위의 범위 내의 방법 및 구조 및 그 등가물이 이에 의해 포함되는 것으로 의도된다.
실시예
본 발명은 하기 실시예에 의해 더 구체적으로 설명될 것이다. 그러나 본 발명은 이들 실시예에 의해 어떠한 방식으로도 제한되지 않음을 이해해야 한다.
실시예 1: 차세대 서열분석을 사용한 RNAseq에 의한 SCN1A 전사체에서 NMD 유도 엑손 포함 이벤트의 확인
SCN1A 유전자에 의해 생성된 전사체의 스냅 샷을 밝혀 NIE 포함 이벤트를 확인하기 위해 차세대 서열 분석을 사용하여 전체 트랜스크립톰(transcriptome) 샷건 서열분석을 수행하였다. 이를 위해, HCN(인간 피질 뉴런)의 핵 및 세포질 분획으로부터 폴리A+ RNA를 단리하고 일루미나의 TruSeq 스트랜디드 mRNA 라이브러리 프렙 키트(Illumina's TruSeq Stranded mRNA library Prep Kit)를 사용하여 cDNA 라이브러리를 구축하였다. 라이브러리를 페어-엔드(pair-end) 서열분석하여 인간 게놈에 맵핑되는 100 뉴클레오티드 리드(read)를 생성하였다(Feb. 2009, GRCh37/hg19 assembly). SCN1A의 서열분석 결과는 [도 2]에 나타낸다. 간략하게, [도 2]는 UCSC 게놈 브라우저(UCSC 인포매틱스 그룹(UCSC Genome Informatics Group, 캘리포니아 대학교, 산타 크루즈(미국 캘리포니아주 95064 산타 크루즈 하이 스트리트 1156 소재) 바이오 분자 과학 및 공학 센터(Center for Biomolecular Science & Engineering))에 의해 운영되고 예를 들어, 문헌[Rosenbloom, et al., 2015, "The UCSC Genome Browser database: 2015 update," Nucleic Acids Research 43, Database Issue, doi: 10.1093/nar/gku1177]에 의해 기술됨)를 사용하여 맵핑된 리드를 시각화하여 보여주며, 및 리드의 커버리지 및 수는 피크 신호에 의해 추론될 수 있다. 피크의 높이는 특정 영역에서 리드의 밀도로 주어진 발현 수준을 나타낸다. 상단 패널은 스케일링할 SCN1A 유전자를 도식으로 표현하여 나타낸다. 100종의 척추동물 종에 걸친 보존 수준을 피크로 나타낸다. 가장 높은 피크는 엑손(검은 박스)에 해당하는 한편, 대부분의 인트론(화살표가 있는 선)에는 피크가 관찰되지 않는다. 중간 패널에 나타낸 인트론 20(NM_006920)에서 보존 피크가 확인되었다. 보존된 서열을 검사하여 3' 및 5' 스플라이스 부위(밑줄 친 서열)의 측면에 위치한 64 bp의 엑손 유사 서열(하부 패널, 회색으로 강조된 서열)을 확인하였다. 이 엑손의 포함은 프레임 시프트 및 엑손 21에 조기 종결 코돈의 도입을 초래하여 전사체를 NMD의 표적으로 만든다.
예시적인 SCN1A 유전자, 프리-mRNA, 엑손, 및 인트론 서열은 표 2에 요약한다. 각 엑손 또는 인트론에 대한 서열은 표 3에 요약한다.
[표 2]
Figure pct00005
[표 3]
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실시예 2: 시클로헥시미드 처리를 통한 NIE의 확증
DMSO 처리(CHX-) 또는 시클로헥시미드 처리(CHX+) 마우스 Neuro 2A 세포(도 3a) 및 RenCell VM(인간 신경 전구 세포)(도 3b)의 세포질 RNA 및 엑손 20 및 엑손 23 내 프라이머를 사용한 RT-PCR 분석은 NMD 유도 엑손(20x)에 상응하는 밴드의 존재를 확증하였다. 생성물의 동일성은 서열분석에 의해 확증하였다. 밴드의 밀도 측정 분석을 수행하여 총 SCN1A 전사체의 퍼센트 엑손 20x 포함을 계산하였다. NMD를 억제하는 시클로헥시미드(CHX+)로 RenCell VM의 처리는 세포질 분획에서 NMD 유도 엑손 20x에 상응하는 생성물의 2배 증가를 초래하였다(연회색 막대, CHX-와 진회색 막대, CHX+ 비교).
실시예 3: SCN1A 엑손 20x 영역 ASO 워크
2'-MOE ASO, PS 백본을 사용하여 3' 스플라이스 부위 바로 상류 서열, 3' 스플라이스 부위에 걸친 서열, 엑손 20x 서열, 5' 스플라이스 부위에 걸친 서열, 및 5' 스플라이스 부위의 하류 서열을 표적화하는 SCN1A 엑손 20x 영역에 수행된 ASO 워크를 도식으로 표현하여 [도 4]에 나타낸다. ASO는 한 번에 5 뉴클레오티드를 이동시켜 이들 영역을 덮도록 설계하였다. SCN1A를 표적화하는 ASO의 목록은 표 4에 요약한다. ASO의 서열은 표 5a 및 표 5b 및 표 6a 및 표 6b에 요약한다.
[표 4]
Figure pct00014
[표 5a]
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[표 5b]
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[표 6a]
Figure pct00020
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[표 6b]
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실시예 4: RT- PCR에 의해 평가된 SCN1A 엑손 20x 영역 ASO 워크
ASO 워크 서열은 예를 들어 RT-PCR에 의해 평가할 수 있다. [도 5a]에서, 대표적인 PAGE는 짐노틱 흡수에 의해 RenCell VM 세포에서 모의 처리된(Sham), SMN-대조군 ASO 처리된(SMN), 또는 실시예 및 [도 4]의 설명에서 본원에 기재된 바와 같이 엑손 20x 영역을 표적화하는 20 μM 농도의 2'-MOE ASO로 처리된 SCN1A의 SYBR-세이프 염색된 RT-PCR 생성물을 보여준다. 엑손 20x 포함(상부 밴드) 및 전장(엑손 20x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였고 퍼센트 엑손 20x 포함을 막대그래프로 플로팅한다(도 5b). 검은 선은 Sham에 대하여 변화없음을 나타낸다. 또한, 전장 생성물을 RPL32 내부 대조군에 정규화하였고 Sham에 대한 배수 변화를 막대그래프로 플로팅한다(도 5c). 검은 선은 Sham에 대한 1의 비율 및 변화없음을 나타낸다.
실시예 5: RT- qPCR에 의해 평가된 SCN1A 엑손 20x 영역 ASO 워크 .
[도 6]에 도시된 바와 같이 SYBR-세이프 RT-PCR에 의해 평가된 동일한 ASO 흡수 실험을 사용하여 얻은, RPL32로 정규화된 SYBR-그린 RT-qPCR SCN1A 증폭 결과는 Sham에 대한 배수 변화로서 플로팅하며, 이는 SYBR-세이프 RT-PCR 결과를 확인해준다. 검은 선은 1의 비율(Sham에 대하여 변화없음)을 나타낸다.
실시예 6: CXH 처리된 세포에서 선택된 ASO의 용량 의존적 효과.
[도 8a]에서, 대표적인 PAGE는 RNAiMAX 형질 감염에 의해 Neuro 2A(마우스 신경 모세포종) 세포에서 모의 처리된(Sham, RNAiMAX 단독), 또는 엑손 21x(마우스 명명법, 인간 엑손 20x에 해당)를 표적화하는 30nM, 80nM, 및 200nM 농도의 Ex21x+1 2'-MOE ASO로 처리된 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물을 나타낸다. Ex21x+1(마우스 명명법)과 Ex20x+1(인간 명명법)은 동일하다. 엑손 20x 포함(상부 밴드) 및 전장(엑손 20x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였고 퍼센트 엑손 21x 포함을 막대그래프로 플로팅한다(도 8b). 또한, 전장 생성물은 HPRT 내부 대조군에 정규화하였고 Sham에 대한 배수 변화를 막대그래프로 플로팅한다(도 8c). 검은 선은 Sham에 대하여 1의 비율 및 변화없음을 나타낸다.
실시예 7: 선택된 ASO의 안내( IVT ) 주사.
[도 9a]는 PBS 주사된(1μL) 좌안(-) 또는 10mM 농도의 IVS20x-21, Ex21x+1, IVS21x+18, IVS21x+33 또는 Cep290(음성 대조군 ASO; Gerard et al, Mol . Ther . Nuc. Ac., 2015) 2'-MOE ASO 주사된(1μL) 우안(+)으로부터 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물의 PAGE 겔을 나타낸다. Ex21x+1, IVS21x+18, 및 IVS21x+33(마우스 명명법)과 Ex20x+1, IVS20x+18, 및 IVS20x+33(인간 명명법)은 동일하다. 엑손 21x 포함(상부 밴드) 및 전장(엑손 21x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였고 퍼센트 엑손 21x 포함을 [도 9b]에 플로팅한다. 흰색 막대는 ASO 주사된 눈에 해당하고 회색 막대는 PBS 주사된 눈에 해당한다(각 그룹에서 n = 5). 전장 생성물을 GAPDH 내부 대조군에 정규화하였고 PBS 주사된 눈에 대한 ASO 주사된 눈의 배수 변화를 [도 9c]에 나타낸다. 검은 선은 PBS에 대하여 1의 비율 및 변화없음을 나타낸다(각 그룹에서 n = 5).
실시예 8: 선택된 ASO의 뇌실내( ICV ) 주사.
[도 10a]는 주사되지 않은(-, ASO 없는 대조군), 또는 300 μg의 Cep290(음성 대조군 ASO; Gerard et al, Mol . Ther . Nuc . Ac., 2015), Ex21x+1, IVS21x+18, IVS21x+33 2'-MOE ASO 주사된 뇌로부터 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물의 PAGE 겔을 나타낸다. Ex21x+1, IVS21x+18, 및 IVS21x+33(마우스 명명법)과 Ex20x+1, IVS20x+18, 및 IVS20x+33(인간 명명법)은 동일하다. 엑손 21x 포함(상부 밴드) 및 전장(엑손 21x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였고 퍼센트 엑손 21x 포함을 [도 10b]에 플로팅한다(n = 6(각 표적화 ASO), n = 5(Cep290 ASO), n = 1(주사되지 않음, ASO 없는 대조군)). 엑손 21 및 22 접합부에 걸친 2개의 상이한 프로브를 사용하여 태크맨 qPCR을 수행하고 생성물을 GAPDH 내부 대조군에 정규화하고 Cep290 주사된 뇌에 대한 ASO 주사된 뇌의 배수 변화를 [도 10c]에 막대그래프로 플로팅하였다. 검은 선은 Cep290에 대하여 1의 비율 및 변화없음을 플로팅한다(n = 6(각 표적화 ASO), n = 5(Cep290 ASO), n = 1(주사되지 않음, ASO 없는 대조군)).
[도 11]은 C57BL6J 마우스(수컷, 3개월령)에서 선택된 ASO의 뇌실내(ICV) 주사의 예시적인 용량 의존적 반응을 도시한다. [도 11a]는 300ug의 Cep290(음성 대조군 ASO; Gerard et al, Mol . Ther . Nuc . Ac., 2015), 또는 33ug, 100ug, 및 300ug의 Ex21x+1 2'-MOE ASO 주사된 뇌로부터 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물의 PAGE 겔을 나타낸다. Ex21x+1(마우스 명명법)과 Ex20x+1(인간 명명법)은 동일하다. 엑손 21x 포함(상부 밴드) 및 전장(엑손 21x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였다. [도 11b]는 [도 11a]의 데이터로부터 퍼센트 엑손 21x 포함을 플로팅한 그래프를 도시한다(각 그룹 n = 5). [도 11c]는 엑손 21 및 22 접합부에 걸친 2개의 상이한 프로브를 사용하여 수행된 태크맨 qPCR 분석 결과의 그래프를 도시한다. 생성물을 Gapdh 내부 대조군에 정규화하였고 Cep290 주사된 뇌에 대한 ASO 주사된 뇌의 배수 변화를 플로팅한다. 검은 선은 Cep290에 대하여 1의 비율 및 변화없음을 나타낸다(각 그룹 n = 5).
[도 12]는 C57BL6J 마우스(생후 2일)에서 선택된 ASO의 뇌실내(ICV) 주사의 예시적인 결과를 도시한다. [도 12a]는 주사되지 않은(-, ASO 없는 대조군), 또는 20ug의 Ex21x+1 2'-MOE ASO 주사된 뇌로부터 마우스 Scn1a의 SYBR-세이프 염색된 RT-PCR 생성물의 PAGE 겔을 나타낸다. 엑손 21x 포함(상부 밴드) 및 전장(엑손 21x 배제, 하부 밴드)에 해당하는 2개의 생성물을 정량화하였다. Ex21x+1(마우스 명명법)과 Ex20x+1(인간 명명법)은 동일하다. [도 12b]는 [도 12a]의 데이터로부터 퍼센트 엑손 21x 포함을 나타내는 그래프를 플로팅한다(각 그룹 n = 4). [도 12c]는 엑손 21 및 22 접합부에 걸친 2개의 상이한 프로브를 사용하여 수행된 태크맨 qPCR 분석 결과의 그래프를 도시한다. 생성물을 Gapdh 내부 대조군에 정규화하였고 ASO 없는 대조군 뇌에 대한 ASO 주사된 뇌의 배수 변화를 플로팅한다. 검은 선은 ASO 없는 대조군에 대하여 1의 비율 및 변화없음을 나타낸다(각 그룹 n = 4).
실시예 9: 드라벳 증후군의 치료를 위한 핵 유전자 출력의 표적화된 증강
드라벳 증후군(DS)은 중증 발작, 인지 및 운동 장애 및 사망을 특징으로 하는 파괴적인 소아기 유전 질환이다. DS의 주요 원인은 나트륨 전압 게이팅 채널 1형 알파 서브유닛(Nav1.1)의 발현 감소이다. SCN1 비생산적인 스플라이싱 이벤트는 인간과 마우스 사이에서 보존된다. [도 13a]는 지시된 마우스 CNS 샘플에서 퍼센트 엑손 21x 포함을 플로팅한 그래프를 도시한다. [도 13b]는 지시된 인간 CNS 샘플에서 퍼센트 엑손 20x 포함을 플로팅한 그래프를 도시한다. 이 연구에서, 안티센스 올리고뉴클레오티드(ASO) 요법을 이용하여 생산적인 Scn1a mRNA를 증가시키고 결과적으로 Nav1.1 단백질의 수준을 회복시켰다.
[도 14a]는 지시된 용량에서 엑손 21x 포함의 퍼센트 감소를 플로팅한 그래프를 도시한다(그룹당 n = 3 내지 6). [도 14b]는 지시된 용량에서 Scn1a mRNA의 퍼센트 증가를 플로팅한 그래프를 도시한다(그룹당 n = 3 내지 6). [도 14c]는 지시된 용량에서 Nav 1.1 단백질 수준의 퍼센트 증가를 플로팅한 그래프를 도시한다(그룹당 n = 2).
[도 15a]는 지시된 용량에서 엑손 21x 포함의 퍼센트 감소를 플로팅한 그래프를 도시한다(그룹당 n = 4). [도 15b]는 지시된 용량에서 Scn1a mRNA의 퍼센트 증가를 플로팅한 그래프를 도시한다(그룹당 n = 4).
[도 16]은 표적 선택도를 평가하기 위해 생후 2일 마우스에서 ICV 주사를 통해 10ug 용량으로 투여된 선택된 Scn1a 표적화 ASO를 주사 후 5일에 SCN1A , SCN2A , SCN3A, SCN4A , SCN5A , SCN7A , SCN8A , SCN9A , SCN10A, 및 SCN11A의 태크맨 qPCR에 의해 평가하여 도시한다. Ex20x+1 ASO를 사용하여 얻은, Gapdh에 정규화된 태크맨-qPCR 증폭 결과는 PBS 주사된 마우스에 대한 배수 변화로서 플로팅한다(그룹당 n = 3 내지 6).
[도 17]은 야생형(WT) 또는 129S-Scn1atm1Kea x C57BL/6J 교배의 이종 접합 드라벳 마우스(HET) F1 마우스에서 지시된 용량의 선택된 ASO의 출생 2일 후 뇌실 내(ICV) 주사로부터의 주사 3일 후의 예시적인 결과를 도시한다(그룹당 n = 9 내지 14). [도 17a]는 엑손 21 및 22에 걸친 프로브를 사용하여 수행된 태크맨 qPCR 분석 결과의 그래프를 도시한다. 생성물을 Gapdh 내부 대조군에 정규화하였고 PBS 주사된 뇌에 대한 ASO 주사된 뇌의 배수 변화를 플로팅한다. [도 17b]는 항-Nav1.1 항체를 사용하여 수행된 웨스턴 블롯의 결과의 그래프를 도시한다. 생성물을 폰소 염색된 밴드에 정규화하였고 PBS 주사된 뇌에 대한 ASO 주사된 배수 변화를 플로팅한다.
[도 19]는 SCN1A 표적화 ASO의 ICV 주사 후 시간 경과에 따른 마우스의 관상 뇌 슬라이스에서 Scn1a mRNA의 수준증가를 플로팅한 그래프이다. 도시된 바와 같이, 태크맨 qPCR에 의해 정량화된 Scn1a mRNA의 수준증가는 주사 후 적어도 80일 동안 유지되었다(그룹당 n = 3 내지 9).
[도 20]은 드라벳 마우스 모델에서 SCN1A 표적화 ASO에 의해 제공되는 100% 생존 이점을 입증하는 예시적인 생존 곡선이다. WT, 및 129S-scn1atm1Kea x C57BL/6J 교배의 F1 자손인 이형 접합 드라벳 마우스(+/-)는 생후 2일에 20 μg PBS 또는 가려진 ASO(A 또는 B로 표시된 처리)의 단일 용량의 ICV 주사를 받았으며, 그들의 생존을 모니터링하였다. 도시된 바와 같이, A +/- 그룹의 마우스(PBS 처리를 받은 드라벳 마우스)는 대략 생후 16일부터 죽기 시작했던 반면, B +/- 그룹(ASO 처리를 받은 드라벳 마우스)을 포함하는 다른 세 그룹의 모든 마우스는 적어도 생후 35일까지 생존하였다(그룹당 n = 32 내지 39).
[도 18]은 자유 흡수를 통한 RenCell에서의 SCN1A 엑손 20x 영역 ASO 마이크로 워크의 예시적인 결과를 도시한다. ASO는 한 번에 1 뉴클레오티드를 이동 하거나(6 내지 41) ASO 17의 길이를 줄임으로써(1 내지 5) [도 6]에서 이전에 확인된 3개의 표적화 ASO(별표로 표시됨) 주위의 영역을 덮도록 설계하였다. 그래프는 SYBR-그린 qPCR에 의해 측정된 퍼센트 엑손 20x 포함을 도시한다. 검은 선은 ASO가 없는 것(-)에 대하여 변화없음을 나타낸다.
ASO의 서열은 표 7a 및 표 7b에 요약한다.
[표 7a]
Figure pct00024
Figure pct00025
[표 7b]
Figure pct00026
Figure pct00027
본 발명의 바람직한 실시양태가 본원에 제시되고 설명되었지만, 이러한 실시양태는 단지 예로서 제공된다는 것은 당업자에게 명백할 것이다. 당업자는 본 발명을 벗어나지 않으면서 다수의 변형, 변경 및 치환을 생각해 낼 것이다. 본원에 기술된 본 발명의 실시양태에 대한 다양한 대안이 본 발명을 실시하는 데 사용될 수 있음을 이해해야 한다. 다음의 청구범위는 본 발명의 범위를 정의하고 이들 청구범위의 범위 내의 방법 및 구조 및 그 등가물은 이에 의해 포함되는 것으로 의도된다.
SEQUENCE LISTING <110> STOKE THERAPEUTICS, INC. <120> ANTISENSE OLIGOMERS FOR TREATMENT OF CONDITIONS AND DISEASES <130> 47991-719.601 <140> PCT/US2018/048031 <141> 2018-08-24 <150> 62/671,745 <151> 2018-05-15 <150> 62/667,356 <151> 2018-05-04 <150> 62/575,901 <151> 2017-10-23 <150> 62/550,462 <151> 2017-08-25 <160> 383 <170> PatentIn version 3.5 <210> 1 <211> 164521 <212> DNA <213> Homo sapiens <400> 1 ataaataaaa gttgcattcc atgaggagaa aacaaaaaaa cccatcacag tgaacaattg 60 aattgctccg tggacatcat gcctttctaa gcaagcattg aatataggag atgtatttat 120 gataaccaga gacagagtat gtatagcttg gctccatagg ggtggtgttc tcggttccta 180 tgtctacctt ttgtattttc cagcccttcc ctcataatgt tactgggaaa gttaacagct 240 agcataacat tttgaaaacc caaagtgttt atatcaacaa gattattcac agtcaaattt 300 tcccataaat atcactggga cctatatttc ttttaatttt aaccaagagt gaaggtagtg 360 agtatagagc cctggcttta gaaactaacc tttaaaaata atgagataat gacacagtga 420 ataaagatgc atcagggttg agcaaagtta ttttttaaga ttagaaaaac tgattttgaa 480 aatgcaaagg cagacaaaaa ggatcagtca agagggaaag aataaagata gaagagaagt 540 agaacaagtc atggagcaag gtatctgaga atgtagaaat gaatgggaaa aattgatctc 600 tgaaaagata taaaagtatg gattgaagga aggaaggaag gagagggaga gaggaaggaa 660 gggagagagg gaggaaggga gaaagggaaa ggtaggaggg ggaggtaaag taagaaaaag 720 gaaggaaaaa ggaagagaat ggaaggaaag aaaaaggaag gaaaaaggaa gagaatggaa 780 ggaaagaaaa aggaagggaa gggaaggaaa agggaaggga aaagggactt agatattttt 840 cactggatag gaaagaaatt gaggaagttt ataatgatgt cctcttgctt gttgctgagg 900 tgaggggctg agttatctgc aaatatgagg agtgttctaa cggaatgata aaggactcaa 960 gcagttgagt aaaatcaatt gatattgcaa attatccact tgtgatttta agaatttctt 1020 ggtgatgcaa ttttcccatc tatacttgat tgtctagagt attttcctcc tctagtgcct 1080 ttgctgccac actgattaaa tcaatattga ttgacaacct cagtgggata tttccatgtg 1140 ccaggaagaa tagtactatc agcagtaccc aattcatggt ggtttagaaa cacatttatt 1200 ttcttatata ataagaaatt ccagtgcaca catgaagaat atgcaattac cagacatatt 1260 tgctgtcttt agtgcgacaa gtttatatag ttcgagtgtc tgggctttgt gatacagata 1320 tacaaacata caaacttatg cagtagagtt gtctgtccca atggttacta gacttttgga 1380 tttcatgcac cagtaaaata caaatgggag gaccgacacc aggttgccaa ttttccactt 1440 ggctaaataa aatattaaaa ccaatgaccc attatcacgt attctcacca tcatttccaa 1500 agaacattta aacattaaat ggtattagtc tttagaaaat aatctaaaag atacaatttc 1560 aggataaagg tctttaactt ggatatgttc agctttataa atatttatgg cattattctt 1620 aattttctgg cttaactata gacatatgaa aaccttgtca taagggtgct gctctgtgga 1680 gctgtgtttg gaattactat ttatacccac agtgtctggt ccccagctta aacagcaaag 1740 tgccaccttc tgttatccaa atcagatctg tttagcatca aatactgggg tcttaaccac 1800 tatgccgcag atcttttcta aaatattctt attttaatta aacagtgatt attatgaaga 1860 acaaggaatg taatcatttc tgtgactttt caggaagatt actgctagga aatgagaata 1920 gtagttaaaa aaccagtata tattgaatta attaccaaca gtagatctaa ttttgaaggt 1980 agaaattata aagtccaggg catacaaaat atgatagtgt gaacacgcag acataggcac 2040 ttcagtaaca cacagcaaaa aaaaaaaaaa aatcctcccc tttctaaaga cacacacaca 2100 tctatacttt tatctatgtc tgtttacata catacatata tatataaatg taactcattt 2160 ttctttgaac tgattcaaga atgagctgca gacattgttg cattcacccc taaatacttt 2220 agcatgcatt ttcagagaat aagaacattt tctattttca tggaacaggc acactagtct 2280 taacaaaatt aggaaaatta acactattat aatactaata actaataaac agtccatatt 2340 caaatttatt caactttccc aataatatta tttatctgtt attttttaat ttgatattcc 2400 atccagaatt gtgtttagtt gtcatagttc tttgacctca tggaattctt tagcctttct 2460 ttgtctttca tgacattgac atttttaagg agttcagtcc acttatttta tagagtgtcc 2520 tcaatttgat tttccttgta gttagattct ggttttaaaa ttttgactgt gtaccaagaa 2580 gtaatgtggc cctttcagta tatcttatca ggaggcacat agtatcagtt ggtctcataa 2640 ttgatgatat ctttgaaggt attgtctgct gtatttctcc aaagtatact ttcttctgtt 2700 taaattttct acttaataga gaagagatac tttaagatgc tataaatacc ctattcctca 2760 tcaaactttc acccatgagt tttaatactc attgatgatt cttgtatgaa tcaattgtca 2820 ttagggtgat tgccaaatag tgatttttct aactccgtta tttcttctac aattgttaat 2880 taacattcaa ctgcaagaaa cagatttgta cttttcctta tttacttaca tcagtatgta 2940 tttgctgatt cttattcaat gaattataat cttttactat catttatttt gatgctcaac 3000 ttgccccaga tttggccagt gggaagcccc ttctagttgg ttcctgtgtc ttactgacat 3060 gacctcatca ttctttgaag aataattact ttttagcaca gaaaatatca tgccaaatat 3120 ttcaaaatga atatggagat ttatatgatt atgttttacc agttcttctc tttgtatttg 3180 gaaaggtaac agtgagtaat ggcgtggatg ggtagtataa aaagtctgca gggtttatcc 3240 tataattctg acctacctta gttggaaatg ggaatttttt tcagctacta atatatcaga 3300 attaattgtt gtgttgcttt aggattgtga tgttatgaag aggcaaagtc agtccattgt 3360 acaaggatgg gaaaagcctt ttaattactg tcccttttct ggttgaggct atattccctc 3420 ttctggcttc acctgatgac aagggaaggc ttctcgttcc tcagaaattt agatagatta 3480 atttagactg ttaattttac tatctggacc acccgagtaa cctttccatg atatctgtga 3540 attctgcact ggacttcact gtggttcccc cagttactgt ttttctttat ctgcaaaagt 3600 tagcaagatt aagaccccaa gctgaagcaa ggcacatctt tgcttcctgc tgactttcat 3660 gagctgttga atcaccttgt gtcagccagg caggagacag atggcatgct gaaatgaggc 3720 atatagaaga atttcatgaa ggggacattt acaaaagtgt cagcaatgtt aggagaaagc 3780 tacaaggaat acaaaagcac tctcaatgca gcagcagacc tgaaggagca aggggaggag 3840 tgattacctg accccagaga aagtagcttc agttgtatga ggggcagtct gattggagta 3900 tgacttttcg gggaggaatg agtccagtgc caacccagca aagaaggaat tggagaagaa 3960 atattcctat gtcaatcttc tctctctggt gctttcccac tggtgcttct cattggccaa 4020 accaattggg agctcaaagg taggagagcc catttttgca atgtgtagaa gtcacccttc 4080 tgggacacac agaatgatgc agaagcagag agagtggctc tggaggagca aacacagtat 4140 cctacacaca tggcaattct aaatttttaa atgatgattt aagggtttct tttcatagct 4200 caaggggtca tccaccatca ctctggcttc catacttctc ttcctcctag aatcactagc 4260 tatcctctga caccagttct tcctcctaac agagaacaca cctgctgctt gtaattctgg 4320 gaggtcatta ccccctacct ccagtgacat atctacccta ggttttgttg tcaacgtggg 4380 tatgcctctg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgcg cgcgcgctcc 4440 ccttctcccc caatttgtaa tgtaaaaaat ctccatatca ttagaatatt ctgttaacaa 4500 aaagtgactg ggcaaacaat aaaataaaaa atgtaatctt tattagtttt gcacatttta 4560 aatgttggtt agcattattt agcataatag tagcattttc cagcatgcag ttcacgaata 4620 cagtttatct aagtagtttt aaggaaaaga ggagcctatg gtttgcttct gtaagaaaca 4680 caaaatgtcc tgatgtaatt gactatataa gttgactact ctgtttttgt ggaaaaaaaa 4740 attatgaagc ccacattcta tttagaacaa tctagagcag cattactcca aagaaatgaa 4800 aacataaacc gaagtcagaa aaaaagaaca aaaataacat aagcactacc ttcaattcag 4860 ttagtgcagg tactaccaga aatataaata aaattttaaa cccttttcca attgcaaagc 4920 ataatttgga tatgaatcgt gaacctattt tgctccttaa aattgtgaaa taatctaaaa 4980 ttagcaaatg taatttaaaa agcagaaatc tacaactacc cagtcttgtt ttcatgtctt 5040 atttagcaaa tttctttcat gaaaaagtac tatggacaga aagtaagaaa agtgattgtg 5100 atatcaacct gaagataatt tcctcttcat atttatgtac ataatgctga aaaataaaat 5160 aaagtgactt tttacagtat ttatatttgc ttataaaatt ctaaacacat atttaatagg 5220 ttaagcagtg tgttttttta aacatgtctg tacagtctgg ctatatacca tatgttatcc 5280 acttaaaatg taaaaataac caaaaagctg ttaaagtgct gcaaactatt gcttaatgac 5340 ttaaataaat gagatctgtt gaacaatttc cttgacttta ccactgacat atggtttctc 5400 ataaatgaga ttctgagcag tgagagaaac cagatacagc agcatggtaa tataaacatg 5460 cattgatagc atccaaacta tctataaatg gtacagaata cattttatta cctgtgtaaa 5520 gcttgcactc tacatttctt gtggtacata tttgatgcaa taaatactgt gcttaggtca 5580 ttatttgttt gctcaaacgt gcaccacagg gtaaaatgac tatttacata ataaatagca 5640 tttcattaac atatacagtg tcaaccttgc tgagagccga agatggctaa acaaagtgca 5700 ggaaaaagca gaaatttata aagagtaatt ttggtcaatt cagtcttctg gcggtggagg 5760 gtgaggggca atattcacta ttcaggtttt ttttttaata caacaaaaag aaacataaca 5820 tttatgactc caaacatttg aatgaagttt gcacctgcta agatttactg gcctacccac 5880 aaataatcta cttggtctag gggctggatt tcgcaaaaca agatcaacaa agcacctcca 5940 cttatcaccc aattacccct cccagaaata tggtgaaatt taagaatttg tttttcttgt 6000 gactttttct catgcatgat ctctaagtgc agcatgccct catgcaaacc acgactttgt 6060 gtagctggga gggccatgtg gttgccatac cccccaggtg gcatacctgt tatagaggtc 6120 cttagcctat ttctcaacag aaacttcgtt tacaaaaata gtcacatata ataaacacat 6180 ggattaacaa aaagatgaat ccactaacag attccataaa aatgtgacaa atgtggcagt 6240 tgaaatgcaa acagtggata caattactac actaaagtgt ttcatgttaa acaaccccaa 6300 aatcacaggt ttgcacccct tgaaactggt ccctacagtc tgactagcca ttgtgcatct 6360 tatcttcagc agtgtcagct ggtagtgaga acagtaacct cctgtcaagg tcatctcccc 6420 tttacacaga gtcacagttt gctgacaagg ggtcactgtc ttattgtagg cactgacctt 6480 aaggagattt gtgtaaaaac agtcagtttg gcattgacct cctaaaggag tcctgttgat 6540 aaaaatacat caccttcaca ggctgtaaac aatttgtcac ccaattattt ttatttattt 6600 tcatttattt ccctttggct ttttcatctt tgccttcttg ctcatgtttt tccacaattg 6660 gctttgtcac ccggtcatag gaaggtggac aagctgcagt ggacatggtc agatcagttt 6720 tttctgtaat agagttttca tttattctgt caattatcat gtcttctttt ataagaagat 6780 tagccccacc tttgattttg tttttattgt acgtaaagga agcttgtttt acagttcgct 6840 ttaaaaggtg gcgtctgtaa gcacgctgaa taatgacagc agatacttcc tcttgttttc 6900 gttttaaagt agtagtgatt ggctgatagg agaccttgga aggattggaa gccatgaatc 6960 gctcttccat ctgtattcgt agagcatcca tctctccact ctctcctaga acccgctttg 7020 taaaagcaaa taagatatca agacagtgga tccggtcacc actcaccatg ggcaaatcca 7080 tggcaatgag ctggagtttg tttggttgtg gcagattgag aggcggttca agcgcagctg 7140 caaactgaga taatttttca aattccatga actgagttgc atcgggatca aacttctccc 7200 aaacctcata gaacatctca aagtcatcct cactcagagg ctctgcactt tcttcagtag 7260 caacactgaa gttctccagg atgaccgcga tgtacatgtt caccacaacc aggaaggata 7320 tgatgatgta actgacaaaa aagaaaattc caacagatgg gttcccacag tctcccttaa 7380 ctgagcttcc agggttaact ttattagggt cacagtcggg tggcttactg ttgagaatgg 7440 gtgctagcaa tccatcccag ccagcagagg ttgtaatttg gaataggcag atcatgctgt 7500 tgccaaaggt ctcaaagttg aacatgtcat cgatcccaac ttccctctta acataggcaa 7560 agttggacat cccaaagatg gcgtagatga acatgactag gaagagtagg aggccgatgt 7620 taaacaacgc aggaagggac atcatcaaag caaagagcag cgtgcggatc ccctttgctc 7680 ctttgatcag acgtaggatt cggccaatcc tagcaagacg gatcactcgg aacagggtag 7740 gggacacgaa atacttttct atcagctcgg caagaaacat acctatgaat aaacaatgag 7800 aataccaacc agtgaagaaa tcatgcgtta aaataaacat atgtttcttc taaagctcca 7860 aggtaaggtt cagagtcctg aacccagtta tattaaatat gacaactata tataatatat 7920 atataattgt acataatata ttataaatct taattttgaa attcagcaat aatttcaatt 7980 ataaggatta tagtactttt ttttatcttt aagagatgtt tataaactac ttttagttta 8040 tgtaaagtcc caagtcagaa tttaaaaaga aaataagtta aaaatgcaca tttggccgaa 8100 cagtagcagc ccaacagtat aggtacaagt ttatatgtat acagtgactt tttctgaaat 8160 tgccatattc taaattctct atttactcct tttccatctg aaagtattgg tagcttttga 8220 tgctactttc atctccccat gatcttggta cttacttaaa ttccactcta atatttttat 8280 atactcattt atgtatgttc tggtgcattt ctgaaaggat cccaggttga tgctcttttt 8340 agtatcctgt acttaatgtt gtatttcaat tctttttggt ctcctgtacc taacactgta 8400 atctcagtct tcttattttc agcttctctc tccatttgct ttttagataa aaacaatact 8460 tgtaaagtta aaaagaagag ctcaagaaac taaatgcctt caagtttaaa tgcctcattc 8520 tgaaaagacg aagtgtaaga gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gagagagaga 8580 gagagagaag gagacgtgtg agaatacaac ttttatacct tagccacact agttataacc 8640 aaggattata attagtggga atcaaaggct atatacaatg agctggatat aaggccagtt 8700 tcttcagaga ggggagtggc atgaaaatct gtccaacaca ggtgcctcgt tttggatagt 8760 aaaatattga cccaatcata tcatcctgtt tagggaagaa tgaataggcc cacagacaga 8820 tgctttttac tttactagag ctttagtttt gtctaatgaa atgagctatt gctcatgagg 8880 ctagttatgt gttccaggct ttgaagtata gtactgatga tgtcccatgc caccttattt 8940 cccttgtgca tcattatgat aaacccattt ttaaggtagt ctagaaaatc tctacatgac 9000 acttgcagag aacctactat atgcatttgc taatgtttag tccttgtctt tattctcttt 9060 ttatgcaata cttttcctta tcttgaaacc actttccact aatatctata tgctggtgac 9120 tccatgtcta ttctctaaag caattttcgt gagtaccaga ctacatttct agtcttgtta 9180 acagaaccat ctagatacta tattggttct tcaatctcaa catgtcaaaa acatttttat 9240 tttagttaat agcacagttc tagttcaaat gaatgaggtt ttactacatt tacactaagt 9300 atattgttct aaatggatag aataagaaac aatactgaca tatagtagga gacattttgt 9360 taaaaaaaca aacacacttg gataaaatgt atcaaaatat ttacagtgat tatctctgat 9420 tgctgggatg atcttgaatc taatcttgat tgtttcagct ttcactttta tttaactgaa 9480 tttaagaact ttaaatattt cttacctaca atggagagaa tgacaaccac aaaatcaaaa 9540 atattccatc caatggtaaa ataataatgg cgtagagaga tgagtttcag tacacactct 9600 ccagtaaata gcacaatgaa caccagattg atgcgtgaca aaatggtagt cacatattca 9660 ctctggtcat ctgtttccac catcattgtg accatgttaa gacagatgag aatcatgatg 9720 cttatgtcaa aaacttgtct ggttacgaag tcaaagacca ttccttgaaa tttgttctgt 9780 agagaaatag aaatgctttt aacaacaaag gagttttctc atgtgcatta gcattaagta 9840 ctttctgcat taattgactt tctagtttct tgcaaagtag tcattggccc tgatttttgt 9900 aagaatgatt tatagcatat taattgttaa aatttagtta tttaaattgc catttactaa 9960 tgtgtatttc tcagaataac aatcccttat ccaaagaagg tttctgataa aaacaaacaa 10020 acaaacaaac aaacaaacaa aagaaacatt caacactgta tacttcttcc agaggtatgc 10080 aacacatatc aacattttaa gattatgaaa aggtaagaaa cccatttaat ttttttttca 10140 agactttcca atgatcagct ggaccataca tccattttaa aatatagtac tattaatatt 10200 tcacttgttg tattctcaaa taattgttaa ggagaatttg gaatttccaa gacacatcta 10260 taacattatg catttaaata ccacatatgg caatactcat attcttctac caaatagcct 10320 tggctaacat tgtcagacac agaatcctga aactgcacaa ggataatgag accagaatga 10380 catttcctat atgtttatgt caaaaaaaac ttcacgttct ttgtcgttga tctgtgattc 10440 tgcttcccat ttctgccact gctagtcact gaaggccatc tgcaggctta tttctttggg 10500 ccactgagga attctgaggg aattttccaa cttatatttt tcctaaattg ttgtttcatt 10560 tctactctta gtgctaaatt ttaatggaga aagtatatat ttctcatcat tctcaggaag 10620 gcaatattca atcatcacaa tatgaatatt tgctagtagt tttttccttg atgcacccta 10680 ggaattactg aaacctctca gatcatcatc ataaaaatat ttatagtgtg ggataatagc 10740 tgtacatttt catagcaatt tgtttatttc atcatggaag catgagtatt gttatttatc 10800 atcataaact gtaattactg accctgactt ctgcagacat tagtaatacc taactctata 10860 gccatacata tgaatagtag atactggaat tctttcctcc tttaaaacac ttagtatctc 10920 tagtgaaaaa taaaatagaa gtaaggtgtt atttcactca acacttcatt tcttaaaata 10980 ttaggaaatt gcatttctta cagccccatc ccaaggttta cttctttccc tgatattact 11040 tggcaaccat tcttgagttg tgtgattaac tttctcttgt gcacatcaca ttgtctatgt 11100 gtccattggc caattaatat ggattgtaat ggggtgcttc taaatctctt gaagtcaagg 11160 gtgtatcttc tatttcttct tgttcttttt tggtctttaa ttttttttgt tgttaccatt 11220 atcataaaag atacaaacat cacttttaga tgatgctcta caagtgaaag aaattttttc 11280 tactggaaat gttagctact ttcttttttg tgagacaagc atgcaagttt ttgtttttgt 11340 atttttcccc catatcattt gatacttctt actcctggtc gaggtatagg cttttgcggt 11400 tttttcgatc ctaatttttt cattgcatta tagtatttct tctgttcttc tgtcataaag 11460 atgtcttgac ctccaaagta tagaaaagaa aaatcaaact ggttaaaact gtgtcctttt 11520 gtacattttt ttcaatgtta aaatagaaaa tggatggcta aaaaaagaaa tacaaaattc 11580 aactgattag tataattata tctgggattt aaaatgtaaa aaaaattgta ctctttaggt 11640 atgataatat ttaattccct aaataattca aaattgactt tattattatt atcttatgaa 11700 gacaaacacc cccaaatctc aaaaaggtta agtattttac ccaagacctt atgcttagtg 11760 agtggcgaaa tttggttcac tgagataata aatacttggt accttatact atacatacta 11820 cctttatgat gttaaaggca ataattttct tatttaaatg tagcaaagag ttagaggatg 11880 tatactgcaa gacagtttgg agttactcat taaaaaagtc actctaactc tgtcaagaat 11940 tggaggaaag ggataaaaag aaaactggat gagttagtga gagatttagg ggataaatca 12000 gagctcatag catagtaagt atgggacaga ccagtaggga tagaagattg gaacactggc 12060 aagtaagtga aatagagtag cctgatattg acttaagaat actactggta ataagaaaag 12120 ggaattgagg ggagaatgtt ctgtagtcta agaaagcact cattcattat acaaaaagca 12180 aacctactga acaagtgaga tgaagcaaca gtacataaag gaagaaatac aaatggccaa 12240 tgagcattta agaacatgtt caaatgtaat aaaatacata aaagtcataa caattaaggt 12300 tataaaagtc ataaaaatta aaattaaata cagttttcac ctattaaata tcaaatattc 12360 aaaaacagaa tgtttggtga cagtgaggga acggtggcat gggtgttcat acactgatat 12420 tgggagtttg agtagttata ttactctagg ggagtaaaat acttcattgt gggaatttat 12480 tctcaggaaa taattaaagc cttattttct gtccctctct cttttttttt gtacaaaact 12540 ttcaacaagg tactatttaa atcattaaag attaaaaaca atctaaatta tcaacctact 12600 ggggaatgaa taagtaaatt atgataatgc atatatgaag acttaacaaa atgagaaaat 12660 acttatgtta agtctaaagt ggaatttata attatagata aaaagtacaa caataagagt 12720 atgtgcagaa atactctgaa cagaaaacaa aatgtgaatg gcagcagtta cttccaagtg 12780 atgatattta tttactttcc atatgttcta taatgtacat aggtaattgg gacaatcaaa 12840 tgagccttat aaatgataaa taatagtcat acaattcaag actgaaacgg atagcttgta 12900 tttaaatatc ttggagaaag aaatgggaat atataaaaga aatcaatgac agaaaaaagc 12960 gtaaaaataa acactagaag aagcttacat ccagtgccta atttattgca aagaattagt 13020 tggaaaatat attttcaagg gggagtgggt agttgtaggg ataaagtaac aaattgcttt 13080 tgggaaagag gcatattcgg ttgctttcta gttttattct aattattatt ttttaaaaga 13140 tagaaaatgt ttcttgataa tgaataagag gaggaaaaac tttatgaacc tatgaacaag 13200 agtgtggaac acagttattc ttagctttct atagccggaa atatatggat agtgaatgac 13260 agaggaagag gaaggaaaaa tcagttataa tatatactcc cattttgttt ctaaattcaa 13320 gtactcattt ggcagagaaa acactccaag gaataatttt ctatctcagt gggagagaaa 13380 atattagaaa tacttatctt ctttttctgc tggttgaaat tatctatgat gacaccaata 13440 aacaggttca aggtgaagaa ggacccaaag atgatgaaaa taacaaagta aagatacatg 13500 tacagacttt cttcatactt aggctggagt tccacctacc aaaggggaat attttgtaaa 13560 atattaccat acattttagt gctggaaatg tcactggtgc tttttcataa caatagaaaa 13620 aattattctt actaatatgt cagcattttt tttttttctg aatcaactac ctctaaaaaa 13680 catccctgaa attggccttt agggatgttt tcatgtgaaa aatatggcta ttatgacatt 13740 ctaaaatcta tttttataac tataaataca aataatattc ttccatttga acagtaatgt 13800 gctaaatttg caagctttta aggtactgaa ttttagtaat tttaaaatta ttaataaaaa 13860 atttaaaact gtaaatatct acaggctagg tttagaaaca gtcattcatg tatgcatgaa 13920 ataatgtagc aaataagaaa tgagttgttc attcagatgt ttggcacttt accctaaagt 13980 aacagttatt gaatttttca gattaagtag acatagatgg acagtccatt ttataaatcc 14040 tcagttgatt atttaattcc tagattgtgc ttaaaacaaa tgggctatta cttataattt 14100 agtaatggac tgaaaggtca ctatagtttt ttaacagatt catgtccttc taaaagcaac 14160 aaagttaaaa accaactaaa cacacaaaac aaaatataag tgacaaagtg aaataaaaca 14220 actctggagg ttatcaaaat gatattcaac ataaaactaa agctatttga aatgcacttc 14280 aagaaagata acatcaaact ctatcaggtt gaagactgca gggacagagg ttattcttta 14340 tgatgataaa ctaaacagat gggacttgag aatagaaaga tgaaggttga tagaaaatac 14400 tacatcttac aaagttttga agagcaaagt tggaatgagc atgaatttca gtttaggtct 14460 tggagcctga aagaggctga aatcaaataa aataggttta tattttggtg atatacactt 14520 aaaggaatct gttggtcaca gaagtgattg caacattagt aaaggctcca gtcaatttat 14580 gaatgcaaaa atcatataaa aacattcttt tatatggttt aaaataggat tatttgaaag 14640 aaatcatcac agtaatctaa ggctgacaga acaatatcca taacttttca tgctgtctaa 14700 tatggagggt gactatacat ttcaactaat gatagaaatc atatatttct tcaaatttgg 14760 tcccgcacac taaaattact actaattata taatgtgtgg ataaatagga aacaaaatag 14820 aaaatattta aaaggaaaat atttgttagt tactaaatac atgaatttgt tactttggtt 14880 ttcaaaataa ttcatgtgtt gaattatctt agtaagatct ttctgataaa cattgctatg 14940 cttgaatatt tacctgtcac actttttccc aaatatttta aatcaagata gaatcatttc 15000 atttggtcgt ttatgcttta ttcgattaat tttaccacct gatcaatatt gtaaaaagac 15060 ttagaataca aggaatactt acatttctgg aatcaactgc tgcatacatt atatccatcc 15120 atcctttgaa tgtggcctat taagaaggac atgcatgttt tactttggag taaaaataat 15180 ttagacctga tgtttaataa atattcttac tgatataatt ttcaaaaggg aatatttttg 15240 aaagacattt caaaacaaat tttacacaga ttttggacca agacagtatt ttagtatggc 15300 ttttcatttc tagaacacat attgaacaaa atggccattt gatatatcct ccccttgata 15360 accaactcac aagcactttt caattcttta gagttcatgg tgtcatgata tttaaagcag 15420 tattaaaatt tgctggagca ctttttagaa agtcttacaa atgccaacac atgggtcaat 15480 agctctatca gccaaataat tacaacttag atctaaggat catctgctaa aatttatctg 15540 cagggtgatc aaagtgattg aaaatttaag atttctcttt attgtaacaa tgtaaggata 15600 gtaccaggat acataaaggc agggttgcaa ctatcctttt aagaattttg gagcaaaaca 15660 tttagaaata caatcctttt aagaattttg catcaaaaca tttagaaata accccctatt 15720 ctattttctt tctgaaattc ttgaagataa taagttaata tgaataagaa atgtgaacaa 15780 tagtacagca gacacttggc actcacagga tgaaggatac tcaggctaac aacttacagt 15840 aatttgttac ttgtcctggg gcatgaattt tgagtcctgt gggcctaaaa ggattatccc 15900 ttagctagtg agggaggtta gcaaagcctt tagcgtctgt atcacaatat atctttgttc 15960 tgataacgct aacccttgtg aggtggtgga tttcatgaga caaaagctaa gcaagggtgt 16020 gggtgacagc agtgaaaaga aagtaatgat tcctagctag aaagtacaag gcttttgtat 16080 atgaaagaga gagagatgtg ttaaatatgt cagtggctta ggtcaatgat agaacaattc 16140 cattacacac ttggtataga aacaaaaaag tgattcaagg gaccatttca atgacttact 16200 aatcaataga gaggtgattc tataaaagcc aaatgtgaag cagtatttta gagggttttt 16260 tttttttttg gtggcagaat ttatttaata gctttgtgca ggaccatcac tgtattttca 16320 gaattgctta cattttaaag gattgcttaa aatttttaat ttttctttcc tcaaatttat 16380 ggaggaggtg gttgctttag tgatatttac aagtatggtc attagttaag ggttagaata 16440 agtgcccaaa taaatatcat catgtgtcga caatttttaa agaaagcatt cttgctagat 16500 tttttttaac ttttgttttt atttgtcttt agagacaagg tctcactatg ttgcctccac 16560 tggtctagat ctcctggcct caagcaatcc tccagctttg gcctcccaaa gagctaggat 16620 tacaggcatg agccaccatg ccccacccgt tcttaccaga tttaaaaaat ctctatttta 16680 attgcatgaa tattattcag agtagatcaa aaatgttaag aagagaaata agaatttcca 16740 acaaaaaggt gggaagaatt tgtaaagtaa tcatagttga cacctctgga agagctgcaa 16800 aagggttttg accagtgttg gtttgtttgc ttagttagtc ttctggttga acagttgaaa 16860 tcataacctt ggtgagcaaa aattgatttc tgccctaaag acactgtaga accacaaggg 16920 aagaaagaaa ttgtacagtc tttttttttt aagctgagtt ttcaaataat ctggactctt 16980 attttattcc ctgctttgtt gtggtgctgc tgcagctaga agcagaatca aatgaaaatg 17040 tttaaagggc tacctttttt aaatataaat tataaactat ttttcttgga gacccagtct 17100 tagagaccca gtagtgaaaa cattaatatt taggacaaaa tagacttaaa taatggtgct 17160 gaaaggtcat ttgagataag acaacagctg cttttgcttc atttttgttt ctagttgctt 17220 ccaggtataa ttctctctct tttttttttt tttttttttt ttttttagat ggagtttcac 17280 tctttgttgc ccaggctgga gtgcagtggc acccaccgct atgcctggtt ctaattctaa 17340 aacctaaatg tcattcccca aactttgatc caaataatag aactcagcag cagttaatcc 17400 ctaccaatta attacaatcc aattaggtgt attaagtgta tgtgttttgg aagatgatct 17460 atctgttaag tgtattccgt tttggtagct gatcagggaa acaagccttc taatcacaat 17520 aaaaaatggc aaagttactg atttattaat ttacttgttt atatagaaag agcaatatag 17580 aaacaaagaa aatacaagaa aaaagacaaa gaggtctttg tttggtctgg tcactactga 17640 ctatatctgc agtccttaca tgtaataaag ttttcaccca tctgggctca taaacttgta 17700 ctaacaaatt gaaatttttt aaatagaaag aaatatatac tttttcttag gaactaaata 17760 atagatgtat gtcattattt tgttattatt ccaaacaata aaaatattca gagaaaatag 17820 tgttcactta caacttgaag caaagagaga tacccaaatc ctacattatc aaagtttact 17880 ttcacatttt tccatcgagc agtctcattt ctttctatta gttttaggca atcagtatga 17940 ttattcacgt cttcgatgtc aaacctgtca ccagttgtgg tgttaataca gtggtagaat 18000 ttgccagcaa acaaatttac gcccatgatg ctgaaaatta gccagaatat aagacaaacc 18060 agaagcacat tcatgatgga tggaattgct cctaaaaggg cattcacaac cacctaatac 18120 acaaatggaa aaaaagaaaa gtcagaattc ttatctgtta ataaagaaaa aaaattcccc 18180 tagtaatctc tggtctttcc attctttttt tctatcaatg ctatttattc taggatatgt 18240 aaaagcaagg ttcaaaaaaa tcttaaaatt catttttttt tcttaagcaa tacacttagg 18300 aaaacaacta taggcaatat aaccaagaaa tgaaacaaaa atgtttttaa aaaaaaggga 18360 gggagaagca ttaaaaggtt aaaggaaaag gaaaatcaga ggaacttgct gccagatgaa 18420 gtcagaattg tgttatcaga ataaagaaaa gttaaaaagc ctatacagaa gtttaactca 18480 ttttaaaaag gcaatatatt aaagaacaaa actaaaacat ttggacctga gttgatttga 18540 ccaatatatt tttaaaataa cttaaaaatt cagatgataa atataaaaaa tattattaaa 18600 tacctaatat aattgtcttt aattattcat gcattgctat gactaataat ttttgcataa 18660 gaagcaagac aatttgcatt atgtatttca ttagatcatc acatcgttta tttcaagctc 18720 cagtcatgtc agttgtttca tttactgagt ttaattcaaa aaacttattt caaatgaaac 18780 ataatagaaa tcatttctta ggaaaataag aaaaagaggg atgccataca tagttctcaa 18840 atctgatgtg atcacatgaa gttctgtgtt caattattat ctactttttt ttttttctat 18900 agaaggatgt tttccccctc tttacttctg gaccactagt taaaaatctt gagtgttcat 18960 gtttggaaac aacataggga tggcttcctt gctttttcct ccatacctcc cactggagct 19020 gcacaggagt ggctaagagg gaagctaaaa acagacccta aaatgcttat aaggggcagc 19080 tgcctcaaac ttggacatta atagctaagt ttaattccac ctatgtgctt gtattattct 19140 tgtcagtctg atccaatgga agtagtcgtc aaaacatctt ctatttgcca tttgatgcca 19200 gtgtattttt agaacaattt tttttaactg cctgtctgaa aaaaaaatac atgagccaat 19260 ttcttatact tctgatccct gtttaaagcc tgtaaagaac tctaggcctt ctggggaaca 19320 taaaacagtg tgataagtgg gccaaagaaa ataagaatac cagtaatgac aaaggtggag 19380 gggatgagta tgaaaaatta atttggttga gttatccagg cagaaccaaa tgatgtggcc 19440 gatgcaacta ccaagctgac acgtgacact ttgccttatc tcatctgact gtctgcatta 19500 atacaatgga cttcataaat tctcgttata taatttattt taaatggatg aatagaatta 19560 gatttctttc agattagaga tttggaaatt gaaatcaagt tactatttcc cttcttttct 19620 gaatattttg tccactatcc agattacaat gctgtttcta gtgtgtatac acagagtact 19680 aattaaaata cgtattttgc cttcaacacc caatttagag tatgagcaga acactgatta 19740 tctataccta tttctcgatt ttcttttcac attacctgtc tcacattttt tctttgaaac 19800 gtttctcagc tttgccacct cttttccatt ctcacagtca ccacctagaa ctgccctctg 19860 ttatttcata cttgcactgt catctgtctc ctaaccttct ccttcattta atctatgtaa 19920 gatgaattaa tcttccccaa gtcccacttg aaagttattt attggctctc tggtaactaa 19980 caaatatttt tcttaccttg gtattcacat cactccacaa tctatatttc cagttttaac 20040 ttccctggtc atctatactt catgccactt caattaatat aataaccgtg tgctaatata 20100 attgccaggt gattgagatg ccatttacat tgaaattcct tgtctaatag ctcctcttct 20160 gaaatactct cccctcttaa aggctttagt tcaaatagca cttctttcat ggagcctaac 20220 tttgtccccc agtttagcct ccaaaataaa gaggaatgtt ttcccctttg aattcaagaa 20280 tcagaattct agtactgaac agaactgtac agataattca gtattgcgtt ctcatttggc 20340 atatgagaaa aatgaggtta aaacaagtta agttcagaaa gtagcctata aatagcattt 20400 agtgctgttt ccagtctacg tggaagagtt gctcccactt atctggtacc catattactc 20460 tgtactagag ttcagtgtaa tcctgacaga ttgtaagatt ttctaaaaat ttaagatgca 20520 aacatatgtt cgtgaatctt ccagggcctt gagtgtcttg aatataagaa cataccagag 20580 agctttgaat ataggaataa aataatggtt gacaaaaatg aatgggttaa tgaagcaaag 20640 tttagattag tatttattga tcaaagcata atttttaaat gttatttctg aatatgggat 20700 gagaataatt aaggaactga gcacagggag aagtttgtgc ttaggtaata tgtttgagag 20760 gtttactttg aaactgggga ttgatttaga gttaaagcga actctatgga atttatgacg 20820 caagcatgta ctctgcagca gtgcacttca ggatatgatt tgcaaagttg gcatacattt 20880 ggcccagaga aaagttttat tttttttgtg aacataaaat aactttatct tagaaaacat 20940 ctggcacagt attggggagt ttattataca aagctatagt catatttatg atgtattaaa 21000 ttagacaatg aaagatcata gaaaagattg tcttttccca agagttccaa gccattcctt 21060 ggttcagcaa agaaggaggt gtattaactt ttttcagtct caataaagct gcagtaattg 21120 gttcttatgg ggggaagaaa gtaggcagaa ttagtctgaa taaattggaa agaacaaatt 21180 tcaaattgaa ctttcaggct acatgaaagg aaatgtctga gaaaggagct atcttaatga 21240 attaatactg tactagaggt tgtttcttct cagaagcttt tttttcaaaa caatcatcaa 21300 ataaagtttc tctactctag cacaaccaat tctatttctg gttcattacc tgcattttta 21360 aaaataagtc tacactaaat gaaggattga taattaaata tgcaaattca cattagaaat 21420 tttcatacat gcagaaatgt ctttttatct gaattaatta ctttgaactt caaatcaaca 21480 ctattcatga attctagtgc ttctctaata gaaataaaga aaatctatgt gaataaaaat 21540 aaaagtgggc aaagtaggaa tcatccattt ttaagtataa agaagaataa tagaatcttt 21600 cttaaaaatc taaaaaaatt atgttgtggg ttttaattaa gacagttttt ttgtaagcta 21660 tgatatattg gtgatccaaa caaaaattct gactttttct gtctctcgaa tataaactct 21720 tcttcttgta taatacactt aaactttaag aataaataaa atgtagagtt atgtttatgt 21780 atgttttcac tgtgttatgt tttaaaatcc tagaaagtta gttgggagtt acttattcta 21840 agaagtgagt ttatgcctta aattttatct taatactcat gataagacgt ttttgtttta 21900 tttctaggta tgtattctat tctgcataat tcaaataagt ggattttttt attctaactt 21960 tttgtttaca acacaattca catgtgctta ttcaactatt tcttaatata tttttgcctt 22020 gttaacattt tgaaaataac cccatatgaa cttacacaat aaaaaatgag agtggtcaca 22080 atcaatacca gtcttatgaa acctgaaata ttgcacccta gtatctgctc atacatatca 22140 ataatcaact gatggtatct aactggtaat tttcaggacc cagaccaatg tactaaacag 22200 caggggctgt atgcctcaaa cagtatcatg agcttaacaa gttaaattgt tttttcacat 22260 aatcattcta caccagggtc ccccgccctc accaatccag taatctcccc aaagatggat 22320 aactccatat acacataact aaatcatatt caatgaaact taataaagat atcaaccatt 22380 ggggttaaaa tccacagagg gtaaattcat aaaggttttt ttttttttca aatgaaattt 22440 aagacaattg aaaagagggg attaggatgt aaataatgta ttttccctac tgtggtgcaa 22500 taatagtacc cttcccaatc cctccctcac cccactacac ataagtcaca gtgcaaggat 22560 taaaggtagc aaaaggggta atacagtacc cataataaag ggctcagggg aggaaccagc 22620 gctccacccc atccaagttg gagcaagatt atcctataca aaatagaaat atatagtttg 22680 ttattagtta gaaatctgat atgacagaac atttggtgtt actttttgtt catgatgctc 22740 tccgtctgtt tccctatcca ttaagacttg agttcttttg aaaaagaagg tatttaagat 22800 ttcctaggtt aggaaattaa aaatacaaat ttaaacacaa attttatttt accctagata 22860 ttcacgacat caattcactc agtttaattt tacaagttga aaaatttgga ctggaaattt 22920 gaaatacaat aaatgtttaa aagctgtcag ccagaaatgt gcataaaaca tgcaaaacac 22980 aaagtgcaac gtgatgataa tttatttgtt actttctaac ttcttatcaa gcactgtaca 23040 acatgcttta ttcagtaatg ttgcataaaa gcacatgctt tgaaaaaata acagaacaac 23100 aaaaataaaa tgagtgcctg agttacgctt tgacgcagct attgtgattt tatgctgcta 23160 gggcaaagaa ttaaatgaga gtttctgagc atgttcaaat ctcacttccc aatcataatc 23220 atcattctta tatccaacct caccatcatt catgattata tttttacaaa ataaaatatc 23280 caaacactag aagtataaaa aatagaatca attataacgt tattttgact ctacaatgcc 23340 aaacacgtat tgaagagatt agtcatttta gtgctgtgtg tatgttgtca ttatgaggaa 23400 tagagccata ttcataaatc tgaccattta aactattagt tatatcacta tcagcattta 23460 taaggatttt atgtctaaaa ctccaagttt caaaaactaa cctcttttaa tataaaaggc 23520 attattgatt aataattata gatatggtta tttctgagaa aattaaaagt ataccgataa 23580 gatcagcttt tttatagaaa tgaagtgtaa tgtatggaaa tatctgagca cttgaccaat 23640 gaatttaata aactttcaaa tggtcaaatg taaaaggttt ataatatttt caaatgttta 23700 gcattgttca gatttcacaa gccatataaa atatattatt ttgattcagg caacatgttt 23760 tcaagtagaa tgtacacaaa tgacattttt tttctccaga actgaaactg ccagtctgaa 23820 acaaaacaaa gtgacattta attggaaaac agacttaatt cttatacacc ccagagataa 23880 tttctgttaa cattttggtg aaaatttgag gctctctgtg agaaataaaa gaggactact 23940 tgtattatat tgttctgagt tgtcgataat gaggacaaag ttttcatata tgttagggaa 24000 atcgaagaca agtcctacgt tcttacaaag tgacatttat aataagactt gagaagagaa 24060 cataaggcta taaacaatct acaaagtgca aatggaagtc tacaatacag cttagtttcc 24120 ataaaagtaa ctacacctta ggaggtgaaa gagcagtgtt tttctattgg aatcacacaa 24180 ttcagtgttt tgttttgata atattttttt ttaaaaaaaa gcagaactaa ttttttatat 24240 tatatatcta taaactaatg cttcatgccg taaaaaaagg catggaaaat aagtcaataa 24300 tggcaaaatt tctaatctgt tatgcatgat ggaaaatgat tattgcatct ttgaaaagga 24360 taaaataaca ttttgtgtga ctctgaccaa taagatgcaa gttaaggtta atgtataaat 24420 tacctatagt aatgagtcaa aattatattt tctgttcatt ataagtgttt tactttattg 24480 ttataaaaat gatgtggatt tgtatgtaat ctttaagtta gtattactag ttttataaat 24540 tcagtcaaca cttaatatct aaccatctaa tcttgaatat attcaaataa tgcaaacttt 24600 ggcattatac agacaaaagt tttaacaact cctttcattt ttttcttaac actcatactt 24660 aggcacatgt gtgattcaca ttattttcag gaaaactcgt taagtacagt atatcatcac 24720 aaagaataag tacctgatat agaatttact ttagattacc attatatcat tacacatagt 24780 actttaataa tgcatcagct tttttttgta tatagatttg taaggaaact cccaagatgg 24840 attaggaaat aaagtcattt aaataagcac agcagataaa tgatattata tcatttcaag 24900 agaggcctat ttctcttgca tatcacctag aagtaaatat gcaacagata aaacaataaa 24960 gtagcaattt tgcaagaatt tgccattcct tttgcatgca tagattttcc tttttctaaa 25020 tttaatttag tttaattttg gctatataca atacttcagg ttctttcatt tttcttaccc 25080 tcatcccttc aaatcgagat aaggctctta gaggtctcag agctcttagt gtcctgagag 25140 atttgatggc tccaagttct gagtaaccca aggcatttgc tgttaaactg accaatgaaa 25200 cctgcacaca caaaaataat aacaattaat aaacagaatc atcattcaat gtgtagttgc 25260 tatataatac aacaagtata atttttgctt ataattattc agaggataaa tgttcagaca 25320 ttttcagtaa acctttaaaa aattaaagaa ataatttcag tttgatgtaa aggatgtaat 25380 ttttaggaca ttaattaaaa gctagttgaa aaaaaatcct taaatgtcat ataatttatc 25440 aactgaataa atagaaaaaa aaagcaaagt aaaaattagt aaaataaaag aagaaatcaa 25500 ggtggaaaaa aattcattgg ctattcttcc tttattttat taagttgctg ttgaatttaa 25560 ggcttttctt gtagctagtt ataaaataca aaaactgctg ttgtactaaa aaaagcagga 25620 agtttctact gtgcatcagt atattcaact aatcataatt ggtattctca gaaattaatg 25680 aactacatca gttttgaagg tgatattttg tcttggtaat accttgcatt ttcacttgtt 25740 tatttttaca taagtaactt agaaagaaat tccattacaa aacttcctca aaatttttta 25800 tactaattta tggcttctgc catgatatct ggccccaaag ggccaatcaa tgaatattta 25860 ccaaatacac acagcaataa atttacttca tttgtattca tttgtaggta atatacatga 25920 ctaaaggaaa aatcttacgt atctaattct ctaaataagg aatttactaa aactttgtat 25980 tcaaggaaga ttataactta tttggttaga aagatgctag tattggagaa ttccgcatat 26040 actgcacact atttttgtaa acttttcttt tttaaaatgt attaattgta tcatatttaa 26100 tatacttctt acattatttg agatgtgctg taattagtcc ttttatagag tgctatactg 26160 atcttcatta aagaattaaa acagaacatt gaaaataaag atattattgt tacaaactac 26220 aaaattttct ataaaattat tttcttaaaa tgtttcaaaa atgacactaa aaaactttca 26280 tgaaaaagct gatgtgtaat aaacataata gaaaaaaaac ctcaggaagt tttaaagggt 26340 taaattacat ttagatttaa attatagtgt aaacaattct gaaattgaaa cataatgtaa 26400 cttctaatgc ttgaaacctc aatattacaa actttctccc ttattgatgt gataaagcaa 26460 ttcttccttt gagatttctc tcaattggct catttcacag taacattgtt aagtttttta 26520 aatagcttag ttttgccttt gttcagggtc aaggaaatat aatgcattca tgattcttag 26580 ctcaagaaac actttccaca agaaaccctc atagtcttgc tgggttagta tctttttggg 26640 gtaaaactac tcaatatgaa atcaggatag ttttgctgta gctttctaaa gctgaaattt 26700 tgccaagttg ataatagaaa acatgatgct taactttaac acatcttgaa gtcagtcact 26760 tgttttcagt aaatgcagta ttaatcattg gggatacaaa ttctataaag ggctgtttgg 26820 gcttgccgta aatctagttt acattctagg aaaactttca ctgctgaata aagtagactt 26880 ctctttccct acactctaca taccttactt cctataatga agtcataatc catataatct 26940 actatttaaa tctactcttt aaaaagtttg agtagatcaa atagaatttt tttaaatgac 27000 tgtagcaccc aacagcatca ctgtttttat tgagtgcctt taatactgta caagttgggg 27060 gtcaagagtt tggggccaag aaactaactc agtggcacaa aatcaacaag tgatggtcct 27120 gggatacaaa cttgagtctg tctgactcac aacataaagg atttaagcaa catacctttt 27180 aagttccctg tttcactact ttccctacaa actgctgatg tgttgttttt tctttagctt 27240 tctcagataa ctagagaact accatagatt ccatccccca atgttatttt aaatcagaat 27300 taaattagcc cttgtcttcc agaaatgaca ctctcattgc atatatgcgt ttagtggtta 27360 ttatagtctg tcaacataac atagtggtct gagactcact attgtagaat ttgaatataa 27420 ataagacaag ctaccttgaa cagagacaaa aatatgaacg atacctacat caacaattaa 27480 gaagtccagc caacaccagg cattggtgaa atatgtttga tagccatatg ccacccattt 27540 tagaagcatt tccagaatga aaatgtaagt gaaaaccttg tcagcatatt ccaacatcgt 27600 cttaatcgtc tttcgctgat caatatatat atcttcaaat gcctataaag aaaatgttac 27660 acattattag ctttcaaaaa taattatact ccataagcta tttaaaaaat taatcatatg 27720 catatgacat ttcattggaa taggagggca gagaaacagt agttactgtt actttttttt 27780 tttcctcgca aaggtctttt acttatttaa tcaggggaaa gactattggt ggaagaaaaa 27840 gaaaagtatg attccaatga attaatttga cttagtcagg aaatagttct tgatgttgta 27900 tcctgatgtg gccatcccaa cttgaagtta tgtattcctt ttgtttcatt tattttgctt 27960 ccttctattg gctttttttt tttttttttt tttttgctat agaaaggagg ttgaagaaat 28020 aatgaaagct tgtgcttttg taaagcagaa attgtgattg atcttcgcag tctccaattt 28080 gactaaatag ttgggttcat ctgcttcttt tttgttgttg tttgttattt ttttaataat 28140 ttatgtttct caacagacat acagtgtgac aatgattaaa tgaaattact tttcatttag 28200 attctaatat atattcttct attatgaacc tctcgatgtt tcacttctaa gtatgcattc 28260 ctttcaacgg tgaaagactt ctaaagtagc gtgtagaaaa tatttctttc ttcagaaaaa 28320 ttacaggtaa atatatgtct gtgttagaat tataaaaagt taaacttgta acacacttgc 28380 atttcaatca ggcaaactct gtttctctct ctttctttct ctttttctat ctatggtatt 28440 tcctttgtgt tagtgtttcc ctaaaatgct atctgtatgt tttatttata gttttataaa 28500 taattttcct ataaaaataa attgattctg atgaagtgaa caccttgtta taaagataaa 28560 cccatcctta aatgaatctc ttgggcatgc tgcccaatat ttattgttac caactttcat 28620 tatttcttaa gtagcacaaa aatagtgagc acacaattgg aaaaagacag agaagtggtc 28680 cctaaggact tactactgtc catcaagaga taataataat aaataccatt tagaaacaaa 28740 attcgtcaga actcagagaa tatatattcc catcccaggg cttccaataa ctttttttaa 28800 ttaaacaatg agtaattgaa tattcacatc ctttggtgtt aatgaataag ctgaagggct 28860 acactttctg ggctatttaa tagtaagcaa aaattaatga ttagcttctt aaaattatat 28920 ttacatacat agtaaaagtt aatccagaaa tatagagtta tagagtaaat ctatagaaga 28980 tacaaggtgg gataattaaa aatgcattgg atactaagac aatgaaacaa aggattaata 29040 agtcatcagt attagagtgt tctaaaaatt agtgctgtat caccttttct taatctcact 29100 caccagagca ccactactaa ggagaatcat gaaaacaatg aaggtctcaa accagttatg 29160 ttcaactatt cggaaacacg tccttctcag gttccaccat tgttttcctc tgccttcttc 29220 cacattgatt tgacaacact tgaatctttg tacacagcct gcagaaagtg ttgaaataaa 29280 agtagataaa gtgtctctgc ttccataata tcctttagca atgtccttgt cttgtctttt 29340 tattactatg ctcatctctg tcttgctagc atagctctct aagcctagag tagtaagagc 29400 acattcatca gctgtgtgaa gttgtggaaa cattcagcca ctttaaatga tgccctagcg 29460 gacagtattt gctttgtctg cctcacagtg ttattgtcca agagaaactt tgtaaattac 29520 aaataaatgt gaggtagctt ttccttgtac catatcatcc tgttgcactc tgttgaagtc 29580 actccagaaa agaactttaa attggacatt aataatgtta agcagaaaac ttccctttta 29640 taaaggatat agagtaaaaa tgtagatctc ttccaacaat gctgcatttg ttaccattta 29700 ggattttttg tgatgtgcct agaagggctt atgtaatttg cataattaat ttagttcact 29760 aaaagctaat ttgtatgatt tggctttgac ttttcattgc cttcctcaca cattgctttc 29820 acttagtcta aatgcaatca acaggtactt ctgagtacca ttgtaagcac aaaggcactt 29880 aggtacacac acaaaaaggc accgaacatg taccttactc ccaagaacct taccaaaaaa 29940 aatctggttt tcaaaaaaaa aaaaaagaaa aagatataaa tacaggatcc ctgctccaag 30000 gcaaaaaaaa aaaaaaggag gaaaagatat gtttgaagaa aaaggagaaa gggaatgaat 30060 ggagaaaagg aggaagaaaa gaagggaagg aggaaagaag gaactaagga gtgaaggaat 30120 ggaggaaaag aagagaaaaa agatagaaaa gtaacatgta actgttcaaa aagagaaaga 30180 gttttcatag gataatgtat attatcgggt aaattaaatg gaaatacttc ttacagccat 30240 tcagaggaac aagctgctgt tccaccatgg tcagatgagg gcagttttga aaaggacatt 30300 aagtgatatg catgatttgt atagggaata gaagaagact gaaggtatac taggcctatg 30360 aaaaaataac atcaaataga aagtatgcat atttccaaac ctcaaattcc cagggatatc 30420 agaccacagg aaatattagt tgtaggaaaa acatatctct tctatctatt gcccatactg 30480 caccaggctc aactagtgac tgtttaggta tagagtttct agggcagtat ttattcccca 30540 tttcatccaa caattattgg aaactgatgt tttcattaaa gaaacacaat ttagcactag 30600 caatccgttt agttttagca gtcagaaagt tacttttaag gcaaattctg tgtaggatca 30660 ttttcagtag tgtctaagat gccaacttat tgtgaaatca ctacttactt taaaaatata 30720 agttagaagt tttgatggta ctaaaatatt tttcctccat gttcttaatc tcttccacat 30780 attgggcaga tataatcaaa gcatgacact agactttaag tttttttgtc tgtcaacata 30840 ttagaggtga ttgaattata tctattacaa agtgccattt tattatatgt gatttatttt 30900 agctgaccaa cagctaaaca agctgcactc caaatgaaag attaacatta ggattctttt 30960 ctttaccttc agtgaaacaa gcttctggtt caagagtttc ttcaggttcc actacgggct 31020 gttcttctac aggtgcgccg atgtccacag tgctaccttc tgatgagcta ctgctttcat 31080 tcagtttctg taagtgagat ggacatagaa agtaaagtcc tttaattttg gtaataagtt 31140 gcctgccaag aaaggattat tactatgaat ttgtttttta ttcttcttga ggtagagata 31200 tttttagaga aaaagagaga ttgaataagg ggaagaaata agaaaatcat tgtctgtgct 31260 aaccctttta ccataattca caatgtaagc ttgaaatcag attgctatgt tatgaggtta 31320 caaaaggcca tcagccacat gtactgagca aaacactgcc ttgtggatta gagaagcagg 31380 ggacacaggg aagagaagag ggaggaagag aaagggaaaa ggagcaggag agaaagagaa 31440 agcttacctt agaagaaaat aatgtcgtta ggttattctg cagtttaatg tttgacttta 31500 catatttctt taacaatgtc ttacctgtgt gtacagatac tacctgttgt tttcacttat 31560 gttactaaga ttcatggtta aggtgttcag agttatttac tataaatgtg gtcatttgga 31620 gagaaattgt tataaaatat gtcaaaaatt acatcaataa acaaccttag agatattaaa 31680 tagacatctt caatttctgg caagtatttt agagcctgaa gtgttgtaaa atgagataaa 31740 tagtgtgtgg gaaaattcag tttcctctga caaatcatgt ttatgttaat gtgccatgtg 31800 aagctgaaag aacaaaatct agttaaacaa caacaacaat aacaatatcc ttcatatttt 31860 gacaatagtg atgggatgca catttctctt tctagagttc tcagaagaca aagatggcag 31920 agataataga aaatattaac taacatatta agataggaaa aactcatgac gctctttctg 31980 aagaccagca aactggctta taagtttttg gcaagtgtaa ttaattcatt aatttattca 32040 actaatattt tttgaacacc aacaatatgc taccagctga gtattcactg ataactgaaa 32100 tatctattgt ccttattgga gtatcaaatc tagtacagta ttttctaaac ttcaggctta 32160 tgtagacccg acaataggca ttccagtgca cacagcagca agccattcaa cccgttatca 32220 cgatattgta aatagtaaaa attaaacaca atattaaaat tgttaatatg aatttcacat 32280 acataggaga gtgttgatat ttcagtaaaa gtttcaccga aatatttgta tttgcttgaa 32340 gaaggatagc ttatatgtct gggtccatat ctagttgcct tctttccttt ccttttaatt 32400 tcttaaaata gaaaaactta cctgacagtt acagaaaatt aggacctata atggcatgta 32460 gctctgtcat agctctgtga attcaggttg aagatgatct ttgaaattat aaaatatttc 32520 tcactgaaga ctaatttcaa cattctaaca cattaaatag gcctgcatac tatgctcaga 32580 agctgaaaag ttgattgttc aacatgatag acagtagtaa atagatcata atctactttc 32640 gggttgcatt tagctttgac tatctttgtg ttctgttcta gcatttgcac tgaatttaaa 32700 acatatccag gaataagtca ttggtttctt cctctgacaa acgaagagaa tcacctagtg 32760 gcaggcgtta gtcacattct caatcaaact actcataaca tcacatgatc ttctgaagaa 32820 attcttatgt cttatcctca acattacaca gattcatcat ttggccgtaa agtgataggc 32880 taagacttgt cacttcaaca agtgccttca tattttaaaa atgaccttga ttggcactat 32940 ccgggacata atgaaattca ttacatactt tataaaaacc atgtgagcaa catttcatca 33000 cccattgttc ttcactgtag aaaagcaaat gcccattctt catgaaacaa ttagagagtg 33060 gaatttgaga attttaacaa ttttcgccaa aattaattaa gaactagaaa ggatattatt 33120 tcctgtgaat aaatttgtgt ggagaggcat tcaggtacaa agaattataa tagcaaacct 33180 accttctata tatataattg ttatctgcta ggtctgatcc ccacatagtt ttccagtcta 33240 taccaagact cacaaaataa tagaatatta gcataaaaat ctactcttca tcagtatagg 33300 ttgtcagtaa taagcagaac aaaaagttgc tcagtaatta atcttcatgt aagtgccaca 33360 gataaatgat tgattctttg cacataagtg ttttatccaa ttgtaaggtg aattagatcc 33420 tggcatgaac atgtacataa aaattgttct tccttgatta ctagtaatat catgcaattg 33480 ttattgcatg atattaaagt atactgatac actgataata aagtattgcc aataactagt 33540 tttgcttttt tgccaaccat atttgttttc ttatgaggaa tactactttt aatgatacct 33600 ctgaagcatt gatttttatt ctgcctttaa gtgaaaccac ttattcactt tatgaattaa 33660 agcattgttt tttacttttt ctaagacaaa gacttatctg acttacctaa gttgtgacta 33720 ttttctgtga aaattacgag aacccaaaag accttatgtt actttttgac acattttcaa 33780 aatggcattc tctgaagaag acaaatagat caacagttca ataagtttta atattcagat 33840 attcatctta tatttcttat ttagacattt atttttagga tgcttaccta agatggtcac 33900 tcttacagaa ttacttttta aaaatacatg tagatttatg gttcttctga tgttttttca 33960 ttagagtctc aattcacaaa aaaacctgag ttttaagttt atatgatttc cattcctatt 34020 ttatcccttt gagttactca accaagatag tgtaatgatg atgtaacaca atatgagaat 34080 aacatcaaaa tggaaaattg aacaatataa gagttggcat gcaattggac atacacgaac 34140 tctaccctgt ctactaaatg ttaggaaagt aaaacttact actaatttta agtacatgag 34200 caagcgcttg taagtaccca tattacattg gtaactcttg aagaatgtag tggatattaa 34260 taacataaga ttgtatgaac tgtatgattg tatgaacatt acaagataat atgaactcta 34320 aattatctta tatttaaaat atgttaaatg tttctgaata actttgctat ttcatgagga 34380 ctactttata aacaaactgg gaccatgggt gggctgtaga tccaggaatt ggtgaatagt 34440 gttacttctc caaattgtaa aacattaatg gcaaagccaa agatagtcac aatggatgga 34500 tacaatatac ttctaagtgt gctttctttt tttaatgcat agagcttgga gtcactccat 34560 atttcagaaa ttttaaggtg atttaaaaga tgatcaaatg cccttattag cattccaatg 34620 gaatatctgc acttggaaag ttcgcaggtc tagacaagtg atcttctaca tgtttacaaa 34680 ttaattttaa aacatttttt aagcaatata agtatattct acagtctgtc tgaactactg 34740 taggaaagtg gaggtgtgcc taataatact caaatttagt atgctctcaa tctaagtaat 34800 gactttttaa acaatcttaa acatacttct ttaaccaaat tcctgattct gcaatatcac 34860 tctttcagca cccagactca aatttttttg tttactttta cttatttcaa acattggcag 34920 taatcaaaag tcagttttcc ttattttatc tctgaaataa ctattttctc agtcagattc 34980 caaattccta tgaaatttct gtttattctt gttacctttt ctttgtttaa ctataaataa 35040 aaatggccat cctcattcta gcctcatgtg acttagacct ttgtggtcca caaagcttag 35100 tgtatgtatg gtgaatgact aacaaacatt tggtgaatga atgaatagat gaatacctct 35160 gtttcagata ttagtgatgg atgaagtttt tgttttcaac ttagagttcc aaccaaatct 35220 cccaaatttg tctttcacag atagaagctg tatgttaatc aaggtgaact tctttttttt 35280 ttttttttga gacagagtct cgctctgtcg tccacgctgg agtgcagtgg cgcgatctcg 35340 gctcactgca agctccgcct cccaggctca tgccattctc ctgcctcagc ctcccaagta 35400 gctgggacta caggcgcccg ccaccatgcc cggctaattt tttgtatttt tagtagagac 35460 agggtttcac catgttagcc aggagggtct cgatctcctg atcttgtgat ccacccgtct 35520 cggcctccca aagtgctggg attacaggcg tgatccacca cgcccggccc aaggtgaact 35580 tcttaatgtt ctctgacttt ttctcctagt gatttttcct cccatcattg cggaagagta 35640 ataattgctc tcttatttaa acccctttca acactttaca gggactactt tgggcatata 35700 ttttattata acttctcttc attctaatgg acttacttac aaaattaatg acacttgcag 35760 ttttctcagt aaaatacaat aactgatgac cttgatgtgc aaaaattgct caggtcgttg 35820 gctactgcct aggatatctg cacatttcta ttttcaccag ctgaatggta tgcttatcaa 35880 gaataagtta tgtttatttt caaatcaatt tacactattc taaaatactg taagtgtgta 35940 atttaatctt gtagaatttg aaaaatgcat ttaaaaagtg ttgttgtatt tataaaaact 36000 aagtcaaaat cattgaataa acgtaacacc ggtaaatccc ccacatagat acatgtacat 36060 taaaaaacca taaaattagg tgtgaatatt tactttttaa atagttacaa atataaattt 36120 ctgagaagat actaaattca ggttgcttta tatgattcgt taagatattt gtcctctggg 36180 ggaaaaaaaa aactaaacag aaataataga tgatgaatta caagtgcagc tcatgctaaa 36240 acattgatgt agcactccaa acaatgaacc catgctggaa caaggcacct aaagtgacat 36300 ttttatacat gtcattttta ttttgtaaat aaatggagca gttgaatgtt tgggatccag 36360 agaagtgtat acatctttca ggaacaatat atgattaaaa attagattta aaaaatggta 36420 ttcatatttg gcttaagctc tacttcgcaa gtcagcattt tgcaaaggga ggctggtaag 36480 ccacatcatg gctaaccctt atgatagacc ctgattctca taatagtaag aagaattttc 36540 ccctactttc aaatcataat aacatcagaa aaagtgacat gtgactatta gaaagattaa 36600 accataagca gtggggctta tgtcaatgaa ttactctaga taaactatga taacctgaga 36660 gaagtgttag tgctttttct agaaatttat atataatgta aataaatgag cattagtgta 36720 agaaaggaaa gaaaaacaaa caaaataaaa taagttcaca agtgaccgaa ctaaactgtt 36780 tttagccaaa acatggggaa caacaagagt tttgattggc atgttaaata aggaatacaa 36840 tacagaaatt aaaattaaat taaacaaata gtaaaccttt tacatagtca atagattaaa 36900 ataaataaaa acattaatat aaaagtcacc cagaccttct caaagatgat agtaagttta 36960 taaaaacaag aaaggcatta agcttaaaca cataatttgt ataaattatt tctaaaatgc 37020 tatatgctta gtctttaatg tactttagaa cttagagaaa gtctatcatc tgcagatcat 37080 aagttgtaca gctaaatttc aatcaacaat tataccaaca ttcagtatgt atgttgcaat 37140 gaaaggcatc tgtcctacta atatgacaga agaggtgttt ccagccaatg ttctccagag 37200 atctcactcc agccttaagt ggctgaaggc tttaattcaa gcagggaagt tccactttca 37260 tctaatttat gcatgataca tgaaaaaatt tgattaaaat attatttaaa agattggaaa 37320 actccctata gtcccagcta cttgagaagc tgaggcagga gaattgcttg aacttataag 37380 tttgggaaca atttcagcat tatagctgga tcccatttct aaaataaata aatacataaa 37440 tgaaaattta aaaaattttg aaaatgtatt ggaaaaccat aattgaatca aaatttgggg 37500 aaatgcatgc ccaaatttaa gaagatgatg ttaaatgaaa gaaaaaatat gtgtggtgaa 37560 tataggggaa attatgtgga atttagtatc atgaatttca gtggaaaaaa ggtgataaaa 37620 tgaaaaaaat cttcaagatt tagcaatttc agatgaaaca acttggcact aagctaatgc 37680 aaagagctat tattttaaaa aggctcttaa agtttagaat ttgtcaccaa caccactagt 37740 aactaggtgg ggggcggggt aataccaagt gaagagacag tatctttgtg ggtattaaaa 37800 aagttatttc aggggtttaa tctataaact tgaagaattg acagtatgtt gaatgacatg 37860 taagaatctc ttctttatgt ctgcaaacat gctttcttca tgacagtctg tagtaagcag 37920 aattctaaga tggtctccaa aatttctggc cactgttgtc atgcccttgt ataatcccct 37980 gcccttatgt atgggcagga cctgtgactt gcttctaacc aatacaatgt ggcaaaagta 38040 atgggatgtc actctggtga tcatgtcaca ccgaatcatt ttagaaaagt tacaatgttt 38100 tcttttttct tcaagaaata aataattagt agttctgact ttttaatgtt aagtaccaac 38160 aaccaggctt acagaagcag caaaatgtga aagctttgct acgtgaaaac atatactacc 38220 aatcaggtaa acttgacaaa ttatactcag gttttttact agaagctgag aggagttgga 38280 attgaacatg acctcagaaa actgcaatat tcagattggt aaagtagacc tggatagtat 38340 aattgatttg gcaaaaagca cacaataggt taaaaaaaaa caaactagga tgcaaaattc 38400 tcaactttaa agctcttttt aaattcaaca tggtgcctct atgaatattt tatagctata 38460 cctcattaca ataagtatgc atattggtca ttttatttgc atatatgcag aatatgtgta 38520 tacattatca tgtggtaaaa tgatccatat atggagtaag tagatgatgt aaattacttt 38580 atacagccaa accacatctg tcactcacca tttctgaatt gactattcca agaactttta 38640 aaacaagtta tggcctccag tggagccaac aaccttattt tttcaccctt ctcctggccc 38700 aggccacagt agtggaaaga aagccaccaa caataaactg gaaagaaacc cagacctggt 38760 ttgacctctt actttctgcg tggctttgct caaataattc ttcctttagc ccatttttta 38820 aatatgtaaa atgaagagat gatctttaaa gttccagctt taattttcta tgactttgta 38880 gtgtttgaga atttgaaatg atacatttgg acagtcttaa atccaagaga gatatgaagt 38940 gaggactgat gagaaggtga tgagggagca gatctggact caggaggaga aaaggatgag 39000 gaagttcaga gtgggtatgg ctgctgggcc tgcacagtct gggtaacatg ttgggactgt 39060 ggctaaaaaa gtcctgtgat cagtctggtc aacatagtga gatcctgctg tccctactaa 39120 aaaaaagaaa aaaaaatgat gttttttttt ttgatacgga gtttcgctct tgttgcccag 39180 gctggagtgc aatggcgcaa tctcggctca ctgtgacctc tgcctcccgg gctcaagcga 39240 ttcccctgcc tcagcctccc aagtagctgg gattacaggc acctgccacc atgcctggct 39300 aattatttat atttttagta gagacagggt ttcaccatgt tggccaggct ggtcttgaac 39360 tcctgacctc aggtgatcca cctacctcag cctcccaaag tgctgggatt acagtgtgag 39420 acaccgcgcc tggccaaaaa tttttttaaa tagctggatg tggtggtgca tgctactttg 39480 gaggctgagg tgggaggacg gcttgagccc aggaggttga ggctgcagtg agctgtggtt 39540 gcgccactgc actctggcgt ggatgaccga gtgaggccct gtctcaaaaa acaaacaaac 39600 aaacaaacaa ataaataaat gaaaaatcct gtgatcatct ctgaccaagg agaagcaaat 39660 agctattccc accttagaga caaagaaacc atccacatgt agctgggctt ttaatttcac 39720 tattagctgt atatgaaata ttcaattact caacatttat tgaaagatac catgttctga 39780 gatttgtgtt aagtatctgt ctcatggatc tccttcatca gcataatgca ttatttacct 39840 gggtttttgt tttgttttcc ttttcatgtt ttgcttttgt ttcttctttt ttattggcca 39900 aattgaaaag cagaaattac actaccattg ttttgatatt aacttatttg ataacaatta 39960 ggagtaatat ttcttaaggt ttgtcttcca gttatatttt ttatgacttg tctcttttga 40020 ctattatttg tttgtttatt tgagacaggt ctcattctgt cacccaggct ggagtgcagt 40080 gatgaagtca cagctcactg cagcctctac ctcccaggtt caagcaattc tgcctcagcc 40140 tcccaagtaa ctgggactac aggtgcatgc caccacaccc ggctaatttt tgtatttttt 40200 gtagagacag catctgatcc tcaggctggt cttgaactcc ggagctcaag caattcaccc 40260 accttggcct cccaaagtgc tgtgactaca ggagtgagcc acggtgcttg gtcttttgcc 40320 tatttttcta ttggagtatt agtgttctta tttgattgca attgctcttt acacatagaa 40380 aatcatttga gttttcctaa caaggattat ttgccaaatg tatttgtttt ctgtgtctgt 40440 gtaacaaatg agcatacacc cagcatctta acatacattc accaactcac agtttctgta 40500 ggtcggaagt ctggcactgc ctagttggat tctctgctca gggtctcatt gagatgatgt 40560 caaggtgttg gctggaaatc cagttctttt ccagggctca ggatcttctt ccaagtttac 40620 tgtcgttggc agagttcatt tctcataatt ataagactgg gcttcctact ttcctgccag 40680 ctcatggccc agaaccactc tcagcaacta gaggccaccc atagtctctg gccacatggc 40740 tgctgtatgc aatttacaat atgggtgttt gcttttttct aggccaggca gagcatatct 40800 tttcagcttc ctctatgtga tagcaggaga aatcactgtg catttaaaga gtttgcctga 40860 ttaggtcagg cccacccagc atcatccccc tttttgtcat aaatgtaatg taattaaagg 40920 gtgataccat atccacaggt tccaaccaca ctcatggagt ggggattata caagggcaag 40980 tgtcattgag atcatcttag aattctgcct gatacaccaa agtttgtgtg tcttactgat 41040 ttttttttcc taagaaccat aacctgttat accaatattg tctgctacat tgataattca 41100 ctattttttc tctttatgta tatcttcttc cttttttgtt ccttttctaa tttctcaaag 41160 atatttgtta ggttctttca tcccttctta atcatattag taatattaag tcatattaat 41220 gactacttgg tcttcttcca caaattttga cataaaatgc ttttattttt gaaatagcta 41280 ttttggtatt ttattatgct tttattcaat atttgtttag gaggcaattt cttaattttc 41340 aaatggttgg aattctttct atcaatttat tattaatttc aggcttaact acattgtgac 41400 tggataaccc tatatgccag ctattttaaa tttattgagc tttactttga actccagtat 41460 atggttactt ttatagaaat attccatgaa cccttgaaaa taaaaatttt ctgtaaatat 41520 gttttttgag ataatataca gtcatattta cttttgctat taatattatc caaaatctaa 41580 atgttgtcat ctatttttta aaatatttta ccataggcta aaaaagttgt attaaaacct 41640 tcataaccag tatatttgca tcaatatatt cttataacgg ttgagataaa agatgaagtg 41700 gtccaattct ttatttgatt gggataataa cactattatt attaaatact caaaaaggga 41760 aggaaaagct cctcttcaga tgtgtaggaa aagtccacct ctatgttagc acatgaaata 41820 cgaattcata taaaattcta aagaaattca ataacggcaa aactaaaata ttctcaaata 41880 agtattttta cagatttaaa aatcagtaag gccaattaat ttttcctttt ttgttcttag 41940 attgaaattt aatttcattt tgaaatttgc tattcactaa taaagtaatt tgttctcact 42000 gttttagaga ttaatggaat atttctcttt ctttctttct tttttttttt tttttttttt 42060 tgagactgag tcttgctctg tcgctcaggc tggagtgcag tggcgtgatc tcggctcact 42120 gcaagctccg cctcccaggt tcatgtcatt ctcctgtctc agcctcccaa gtagctggga 42180 ctacaggtgc ccaccactgc acccggctaa ttttttgtat ttttagtaga gatggggttt 42240 caccgtgtta gccagggtgg tctcgatctc ctgacctcgt gattcgcccg cctcggcctc 42300 ccggaatatt tcttaaaatc tattttaatg tttattaaac catgaatcaa ccttaaattt 42360 taccaatttc taaataggct agtttattta agaatatgta tattttcaca catgaatctt 42420 aatagctaaa ttatacactt atacactgac ttgtatcatc catgtatttt tggcaggctg 42480 acttaatatg tgagctgaca gaatgcagag accacgttgt atatgaagca tccactttgc 42540 cttgtacacc agggcattca ataaccactt aataactaca accctgatgg taagagcagt 42600 tttcctccgc agtggattta tgcaaatttc ttgtttttta acaatgctct ttactatagc 42660 aaatgatttt gaccttgagg gtaaggcaaa acaaagcaag gcaaagaaaa ctttcttcaa 42720 tattctctga gagtaagtga ttaaatgctt tttttcttgt tctctgactt gatcctacaa 42780 tgtttatatt tttattttta aacttggttt gttataagga gcttatttat agagtttagt 42840 aggagttcaa attataataa gtaatataaa taaatctgga atttaagggt caaaagcata 42900 cttaatatgt ggtcatgcga tgtctatata tttgtatatg tatatatgtg tgtacatata 42960 tatttaatat atatatttaa catacacatg tatatattta acatataaag aatattatcc 43020 aaagtactta tttttaaagc tggacaggta ctattttaat gctgggtact ttactattgt 43080 gacacatata tctcctaagt catgctaaaa tgaggttctc tacaacctca gaaatgctag 43140 tattaatatt tcattgtgta cattgtgcac tagtaaatat ttctattgta cactatgcat 43200 attaaaaatt aaaatgaccc ctattaaaga ctctcaacaa aggaaaatat aatatcaatg 43260 gaaaagacac tgtaatgaga ctcaacattt ccacagggca gctagaaaac tcaaatatta 43320 actcattaat tcccacatta ttcccagttg atttcttcat caagctgtat gttgaaagga 43380 caatcttcag tgattattca tatttacaga atgtcagttg tttctattct ttagtcaaac 43440 acttgcccag tataaaagtg aacgtggagg aatacggctc taatatacta ctctgaattt 43500 tgctttcgat aggtcacaca taaacttctg tatcaataat taaatataag ggaacaaaag 43560 caacatattt cagacatatt gagtcaatag aaaatcatgg taatacaaaa aaattggaaa 43620 gaaaacaaaa aaattctgaa aaattgcatt tataatcccc aagctagaaa ccaaaatgca 43680 aatcaaatga gtaattttca ttgttaaatt cattttgcca aattgagcac agagcttcta 43740 taatgttatt ttgacattga tttttaatgt taaattataa catacttaat aagtgtctac 43800 tgggcaaata aactgtatat ctatataatg aaagagttga aagtactact gttcagagga 43860 tcagagaaac ttgagtttga atcacaatca ctggttttat ggactttaac caattattct 43920 gacctcctta ggctttaggt ttctaatttg taaaatggtt cttacttcac atccttgtta 43980 taaggactga acaagataac acatgaataa cgtttggcgt atgcttattt gataaatggt 44040 aacaatttcc atcacagtat tgtattgttt gtaataggtg taattattga tatttgaact 44100 ttttcactac caaaaatgtg ccaggcatca aaactaggac ttgaaaaata aaatagtgaa 44160 cataatagac ttagtatctg ccctcgtcgg ttcacaatca gatggaggat acagagaagc 44220 aattgccaca cactctaata ggagtagtat agagtatatt gagaacacca cctagctcaa 44280 tctaggaagg acagggtaga ataaagtgac atttgggaca agaaggatgt ggtgggtgag 44340 gatgagtcag gtgaagcagg atagagtaag agagtattcc tgtcagagag aaaaggtata 44400 acgatgagaa ctgataaagc atagggaatt acattgaatg aaagattagt atagctgggt 44460 ggggaggtgt gaggtgtact attccatgat actgaaggag tcagcggtgg tcagttttgc 44520 agggacttgt acccatgtta agtagtatag actccatact gtgagcaatg ggcaactcct 44580 gaaaggttag ggaggacaga acggttacgg gatttgcatt ttagaaagac cacctattgt 44640 tttgtcaaga ctacactagc gagaggagac ccgtttggag gctgtagcag taaaactgga 44700 agatgatgga ggtctgacac tgggtaaagg ccttgggaat gcagagaggt ggacaaagat 44760 aggtagcttt ggcagtccct agtgatcaat tagaagtagt ggagatagta ctcttgggtt 44820 ccatggatag tactcttcgc agagagtagt tgccatctct tagagactat gtgcttaggt 44880 tggagattgt cgtatgttcc ttaacccata taacgtaaga taaaagtatt agatggaaaa 44940 atatcagcaa agcaacaagt agatttaaaa tgcatatata tcagtgatat aattgggaaa 45000 aaatggaaat ctagaagtaa ctgcccatca cctatttatt cattcattta ataaatatgt 45060 tgtatgtgct gtggacttaa gggaagacag ggttagtgtt tttcctgttc tcaaagacct 45120 cataagctaa tgatacatca tagaagttct tcctaatgat ttggaagact cttccagcag 45180 ctttaaactc agaaggggat gctccttaag cacaactatc acactctggg agactaagtg 45240 ctctctaagt agaattagac caccacaggt cagtgtggga tgcagaagca gatcagccta 45300 aagtgcaggc cagtaccaga ggaacaggac ctttcaggac taagcaggag gactctgaaa 45360 cactccagac tatgctgtta acctatgccc aatgtgcagt gattggaagt taacaccaaa 45420 tctatagttg acacctgtac ctagttcttc aacaaatagt attatttatt tcagaactat 45480 gccaaagaaa gtacattttc agacactatt aagatttagt gtagcggtta agagcgtgac 45540 tctggagcag actatggagc agactgccag gaccaaccac ttactgtttg tgtaactttg 45600 gcaagttttc ctttgttcaa aatatgttta tttttctcat cttaaggctg gaataacagt 45660 gtgtcttacg gcataaagac tgaatgggac aatatatgcc ctccaatagt actttgtcca 45720 tggtgaacat ttaaacaata gctgttatta acataacctg aattactaag gacctcacat 45780 ttttactcat tattctagag ctcactcatc gcaaaaacaa atgtatttct tttataatta 45840 ctttagtaat gtgccttttt tgttcccaaa aggtacaact ttaataactc aatttattta 45900 aaatttttat ttaaatggaa ttaagtagta attttcttga catcacctta cacttttgaa 45960 catttttaac ttccaaatag cttttagatc ttcataacat ttctataagc atcataggac 46020 agatatctca tttaataaat taggaaacgg ggtaatatag atttagcgat ttgctcatag 46080 tagagttaag gcttataagc tcttaatcta gtatccatat aaatcaacca aacctcaaaa 46140 aattattggg caactgttat gcacccagca ttgtggtagg tgcttcggag gatagaaatg 46200 ttataaaata ctatccaaaa ccaaaataaa tttactttct atttggggag ataagatttt 46260 atattgtctt ttgcatagtc ttggcagttt tgcccagcct tcaaagctct ctcagatctg 46320 tccaagtcac cattctttat tattaatgtt caataaaaat tcatgtttct agcttatcat 46380 tattcctact atggcatgag tcaagaaatt ttctgaggtt ttaaaaaaca attcctcaaa 46440 ttacttgaat gtactttgaa ggttgaagtc tcttaggact taaagagagg atgaaatgtg 46500 actcatgcta ttccctttct tcttttggag accaatagga ggaaggtgta gaaaaaacag 46560 cccttagttt gctctggaat ggaggatagt taggtgtgag ttcaccacag atgtaagagg 46620 caaaataaat atgaggttcc agttcaccac atctcttcat accagtctat tcttgcttcc 46680 tggaaaccaa gactctttac ctacatctca tcctcagctc ctgtgattta cgcccccgga 46740 attccaaact actaattgtc tccaaataca tcctcttgct tcctgtcttt aggtttctgc 46800 atgtttgtat ttcctgattg gaatgcccct tagaaaagta attttcttaa atattttaag 46860 gagcttacca tatcaagaat gtaatcaaaa caatttaaaa ataaacagaa aatataaaat 46920 gtatcaccat ccccagataa acttataaaa caatttatta cagagggcaa aaggcaaaca 46980 acaaaaaaag acaaatagtg gagtatgtta ccagtagtaa ttcttgtaag aaaacttact 47040 ggaacagtgt ggaatgcaac tggtaacaat aataatgatg atttaccaga tattctatat 47100 taattaggca ctgtgctaag tacttcacat ttattatctc atttaatact ctgtcccaga 47160 aatgcagtca gtaacattat gcacattttt gagatgagga aactgattat tagataggta 47220 aagtcacaca gtaagcggct aaaatgaaat tatataaccc agtatctggc tccagagtat 47280 aaccatttac caactttata actgtggcct cacatgtcta aaaacaaata tttagtgtat 47340 gaagaataaa cagtgggcac ttgtaatttt aacacaaggc attaatataa ttttggaggt 47400 attataatga tgcattgtag ataagtcatt actggaattc aggaatggaa acaataacat 47460 gttcaaatga aactagtcta atagaggcca tgaaaggtaa catttttgca tcagtaacat 47520 atgtctcaat atgaaaattc atacttaaag gttgaaagtc atacacacac acacacacac 47580 acacacacac acacagagac agagagagaa aatcattcct tatagcttat tagtatactc 47640 ctttatctag tctccctggc atatgataac tgataaataa atgaaaatag gcaaaaagaa 47700 taaaggctaa aacaaaaaga accaaaatga tgagattaat atactacagg cagcattcct 47760 aatgtagaac aaagactctt catctattgg ggcatctgct gtcagcttaa ttcctctaaa 47820 agcagaatat ctcataattt atgccttact ttgatgaaca gaatacagta taagactgat 47880 gaagcaatga gggcaaacaa tattgtgtgg gtttatttct gaccaagaag aaaggaattg 47940 tgaagtaaaa gtgccaggaa atttgataca atgtggtaat ctgtgaaaga atataaaaag 48000 aaagccagat tcaaaaatga ataaaagaaa ttgaaatgta tcattagggg ataaatagaa 48060 gtttcagtat ttaattacaa aatttcgtct ggatgagata caactgcatt tcaacagcaa 48120 ttcatgtgga aaagatgaga gattattact ttcttagaag ggtggtgtaa agtgacaagg 48180 taacatggct aacaaaaaca aaaacaacaa aatctaactc aagtgaatct tgaatctaga 48240 gaaaaaattg gtccaaaata attggaatta aaatgacaat ctcaagtatg ctctaatcag 48300 agaaagtatt tatgagagcc cttcagaatg gttttattaa gaagagttga atgagctgga 48360 aaagtttgat ctgagtgtct actttgtacc aaacatgttt aagtaggtca ccacataaaa 48420 ggagagacat gcatgcatat aagtagctac cctaaaatat gatagtactt tgtaagacgc 48480 atgagtcaag aagatgcatt atttattact atactctatg ccttatatct ctgggaacca 48540 aaaaagaaag caatctgttc tgcctagggt taggaaggct tcattatcac taccttcaaa 48600 aagctgaaac agtctttctg aagcttaaga actcctggac ttcagacact atgcccatga 48660 accaagtggt tgcattctaa ttagacaaac aaaacattaa agttcagcac aggtggcaaa 48720 agcttcattt accaggactt ctccctctga catgaaatgt gctctaacgt tattctgttc 48780 tatttcattg gccgggtgca gtagctcaca cctgtaatcc cagcactttg ggaggctgag 48840 gtgggcggat cactatttca ttaaaattaa aaaaaaaaac tggcctatta aagggatttc 48900 tcaagtctaa ctaaactatg actcacaatt tgagaagcac cacattaaat tatctctaaa 48960 gtttctatta ccttaacatt taaaatttca attaatgcaa tgttccaaga tataaaatac 49020 cacaaagtag aaagaaacag aactacctct agtgcttcag tggatagttg ctttataaaa 49080 aggttagtgt ttcttttagc cttgatcaat ataaaaaaac aataagagta agaatcatgt 49140 caaattttta cagaaaatgt atatcttatg gatggtcttt gtaaaatagt ctttttcctt 49200 tttaatataa cagatagcat atggtagcca ttagtcctca tcaaatgcta aatgtaggtc 49260 taaagattca agacaaagga agctagacta ggctattact aaatttattt taacagaagt 49320 tcagaaacaa ttttataaag acaacaattt ttcaaaaaat tagccttcat ctgattcctt 49380 aggaaaactc aaataaacaa agtctgaact gacataatat ccaaattaaa atttctgtaa 49440 aaaagtccac aatatttgat aaaaacagtc tatttttttt ttgtcctgaa tctatttcca 49500 tagacatgga aatgtgacag gatctatcta ctattacatc tctgcactat atttctttcc 49560 cttctctcat caaacaaatc tgaattaact aagcagctct aatgctaggg tcagggcagc 49620 tgcttccagc tccaatatta gccccctact cctaaaagtg gaggctgacc tagattattc 49680 agagactcat tataaatact tgaagcatct tttaagggat atagtcacta aatcaaaaga 49740 atgtcacata cctgtggtat cttccatgga caactatcaa aatgcaatgg acatgatgat 49800 atctaataga attgtatctc taataaaatg tctttaatgt attcaatcct ttaaaatatt 49860 tagactatac agcctaaaag atgggcaccc tgctgttttt gagatttcca aacactaaat 49920 gggaagtaaa ggtgctttgt cctagactcc ttgttaatta tcttatatat ccattagact 49980 tttaacttaa tatttcaaag taggttgcta tggattaaag ttttgtctcc acaaaattca 50040 tatgctgaag ctctaacctt caatatgact gtatttgggg atagggcctg taaggtggtg 50100 ataaaggtta aatgaggtca tacaggttgg actttattct gatagggctg gtgcacttat 50160 aagaagaaga atagacacca gagttctctc tctttccatg tacatgcatt gaggacaggc 50220 catgtgagga cgcagcaagg aggtggctgt ctgcaaccca aggagtgagc cctcactaga 50280 cattgatgct gctggtatct tgatcttgga ctttccagtt tctggactat gagaaaataa 50340 attttggttg tttaagccac ccagttatgg tatagtgtta tggcagtcca aacaggctaa 50400 tgcatagggc agtgtaattt tagttgaagg agctacaaga atatttcttg ttgttaagtt 50460 ctcttcaatg tacatgagcc aatgtgatgc aaaaaacaat aaacagaact tgtaaacaag 50520 ggctctaagt tcaactctcg gcactcccct cactagctat gtgacctaat gctccctaag 50580 ctaattttct tatctgaaaa gttaacataa taacacattt ctttccaggt tattgtaagg 50640 attaaatctg atgatgtttg tctatttgtt agatcgttca ttcattcatc taacaaatat 50700 ccattactaa ggatgagaaa actcacacgt atactatatt accctttaat ttatcagtca 50760 tttccgagtt aaatcttttg ttcctcagtg aaataaaatt ttacatgatg tcaaaaaaat 50820 ctatatggaa aatatataat aataaataca ggcaatataa tgcatgtatt gtaaatgttc 50880 ctcaatttac aatgaggtta gttcctgata aactcattgt gagttgaaaa tattgtacat 50940 caaaacttac ttaatacacc taactaccaa actttatagc ttaccctagt ctactttaaa 51000 catgctcagg aaatgtagat tagcctacag ttgggcaaaa tcatctaaag gaaagcatga 51060 tttataataa actgttggat aactcaggta atttcctgaa tacagtacac tgtacggtaa 51120 atattggttg tttatccttg taatcacgtg gttgactggg agctgcagct tgctgcccct 51180 gcccagcatg agagtatatt gtaccacaaa ttgctagcct gggaaaagat caaaattcaa 51240 aatttagagc atggtttcta gtgaatggct attgcttttg tattatcata aagtaaaaaa 51300 aaaaaaaaat cttaagtcaa aacatcatta agctgaggat catctgtatg tgtgtatatg 51360 tatatatgta tatgtattca taccttccca cacctataga atcttacctc tttgctttct 51420 tccagatccg attcactact aaagtcttcc gtgtttaaat tttcaaagtc agattctcct 51480 acagcaattg gtacagtcac agtaagactg gggttgttta tgaatgacat gtaatcactt 51540 tcatcaataa tgtatttttc aacactgctg ccagttccta taccacttgt agttccattt 51600 acatctttaa gatagtcaag atctttccca atttctgctg tatgattgga catacaactg 51660 tctttcttgt tgtttagatc atcaagtggt ttaatttcat ctaaaatctt ttgtttccta 51720 atgaaggact gttgaataaa ttcatatatt tttcttttca cataagctac tcctttgtgc 51780 atcctatcca cagcaatttg gagattattc atttcattat catcatcagt ggctgcaagg 51840 ttgtctgcac taaatgagct cagaagcaag gccagaaaga gattcaggac cttaaaaaca 51900 acaaaaacat gattataatt ttacaccaat gtagggaaga gcagattaca atcacttatt 51960 ctttctttta agtgtggaaa aaactctaag ttctaaaact tgatgagaag gaaacaccac 52020 agcatagtga ttagaagatg ggtgatctga atttgtgact ggctcaatag cacatccttg 52080 gacaaagaca tgatttctgt tgctctcaag ttctcccatt cgtaaagtga aattgaatga 52140 gctaatctaa ggttttgtta actctaaaat tgtatgagta gaagaaaaca gatttatatg 52200 tgtacaatac gagaattctt aaaaatcact aatgtttcca agtatgcatt taaatgcatt 52260 ctataatttt tcaataaaca aagatattaa attggatgtc aattgaaaaa taaccattac 52320 aactcagaat gaagattagg agcttaacat aggctgacac ttgttttctt aatctattat 52380 atttctcata cttcattgtt gactaagtag agctgtttat gaataatctc tcatatttcc 52440 atgagactgg cacatgaatg tacatacctt tagaatattt tatgtattac tatactataa 52500 acagtaacac tccaaattta agagagataa agattgatca gttactccat tatggtaatc 52560 tcaggcatca ttagccattc gagaactgat gaactcaggt tggctagtgc atctgccata 52620 tgacatagag tgattgaata tcatatgctg caatggggca aagaaatggc acaagcatta 52680 tgaactctta aagacaccac tttttagtcc tagtctggat ggtaattttg cactttctct 52740 ctactttttt tagacttctc tcttccttgg ctctgaattt ataaaatggt cccagcacat 52800 ccttttaggc tcatctcaat atgatactct attgtaattc acataaaaaa tgtgataaag 52860 tgactgacaa aatagaattt ggtataaaaa atgcaggggc actgctatat tgctgtgttg 52920 ttaaagtgat aatatatcca aggtaatgga cttttaaacc aataatcata gtttgttttt 52980 ctttttgaca aaacagtcac cattaaatta tactcttttt ttttattata ctttaagttt 53040 tagggtacat gtgcacaatg tgcaggttag ttacatatgt atacatgtgc catgctggtg 53100 tatttccaaa atgcatatct taagtgggta cataccacta ggtttccaat caccatgacc 53160 atcatgaaga cagtaaggca catggcttga ccagcaacct ccatacagtc ccacatggtc 53220 tctatccact ccccacacag cacgcggaac acaatcagga aggagtggaa gaagtcattc 53280 atgtgccagc gtgggagttg acaatcactg gcgatcttgc agacacaatc tttgtagctt 53340 ttaccaaaga gctgcatgcc gaccacggca aaaatgaaga cgatgatggc caagacgagg 53400 gttaaatttc ccagagcccc cacggaattg ccgatgatct ttattagcat atttaacgtt 53460 ggccaagatt ttgccaactt gaaaactcgc agctggaaaa tgaaagatta atatatattt 53520 gtatgattct taaaagcatt atatatattg agctttacct agaaatggtc attagaattc 53580 aatatcttac aatatctgat ctgccctaac cgtctcaggc tcatggctaa tttttggact 53640 ccctaggaaa agctggattt tccatatttt aaccatgtag atcattttct ctgatggtga 53700 attatttttc tttccttttc tttttttttt tcttttgtca cccaggcggg agtgcagagg 53760 agtgatctcg gctcactgca acctctgcct cccaggttaa agtgatcctc ctgccccagc 53820 ctcccaagta gctgggacta caggcacgtg ccaccacacc tggttaaata tatatatagt 53880 agagacggag tttcaccatg ttggccaggc tggtcacgaa ctcctgacct caagtgatcc 53940 aactgcctca gtctcccaaa gtgctaggat tacaggcatg agccaccaag ccaggcctct 54000 tatagtgaat ttttaatgag tacttggaat ccaactgttc ttaatttgtt ttataaaggt 54060 ggttctaagg ccggatatta taatattaac atctgaatct gaaatatctc tgctgaaaga 54120 tattaatttg ccagtagtgt gcaaagtaac atcatactga gccctgatat aagtaaagtg 54180 ttcattattc attaatgctc cttaggggta ttcatgtagt tacatccacc tgcattgaaa 54240 aacttggaat atttcctata attctacaat tattttcctg acttgtaagg atatatgtgt 54300 gaattaatgg gcatgcttag taatcctaca gactttctct cctttgactt tcgcaagatg 54360 catattttcc agagacagaa ttagaaaaag tttctgcatg cacatcttac atctgatttt 54420 catccactgc tacaaagggc tatatatatt ttcaagttac tattaaaagg tgatgcattt 54480 tcattaaaaa tattttctta ggtctagaaa tattaactgt agtagtctct agaagcaata 54540 cttagtgaaa atagcaactg agtaatacgt taacttttac gtaactatgt tctttgaaat 54600 aaaggttttc ataaataatt gagaattttt ttccatgtag gaaaagtttt tgacaatgca 54660 aatgttacag aaaaacttac aatgctaatg gttgtgtggc aaaaaaacta tgacattgct 54720 atgcaagaac cctgattgtt agaaaggttt ttgaatttgg tgcttttttt tttttttttt 54780 accaatcgaa atgaacggag aacagataat ccttccacat tggcgagtcc aagttctacc 54840 aggctaagcg tcacaataaa accgtcaaag atattccagc cttcttggaa ataatagtaa 54900 ggatccatgg caataatttt cagaaacatt tctgctgtaa agatcccagt gaaaacctaa 54960 gatcaaaaca aaattaatct aattccacca gataataaca tacatgacat aagatttgct 55020 cttagaacat aatgcttatg ctattttccc acaatgattc tattactaac ttaaatttgt 55080 atggcaattt gtagttgatg aaagactttc atatacatta tttaatttta tccttgtgga 55140 aacgcgaagt agataatata caattattac tttacagata aggaaactga ggtcttcaga 55200 tgggtgaaat ggcttgcttg atatcataca gcaagaaaat ggcaaaacta ggatttgagt 55260 acaagtcatc tttttttttt tttttttttt tttttttttt ttgagacgga gtgtcagtct 55320 gtcgcccagg ctggagtgta gtggtgccat cttggctcac tgcaagctcc tgggttcacg 55380 ccattctcct gcctcagcct cccgagtagc tgggactaca ggcgcccgcc accacgcccg 55440 cctaattttt tgtattttta gtagagacgg ggtttcacca tgttaggcag gatggtctcg 55500 atctcctgac ctcgtgatcc gtccgcctcg gcctcccaaa gtgctgggat tacaggcgtg 55560 agccactgcg cccagcccaa gtcatctatt tttaacagtg ctctttccat tataccaaac 55620 tacctttttg tccagacttt atataccaca agtactgaca acattttgcc catgagcact 55680 tttatttatc tataagctta ttcctatttc cctcaatcag agttatacat tcttatctat 55740 tatactaggt gcattactat tgtcattctt tgttatgcac atgaaaaaaa taaatttact 55800 tctgtagtat aaatagtaga acttcaaaaa tataactaat aaaatgcagg ttgttatgca 55860 tgatgctttt gttttctacc atcaaaaatc ctaaacttca aaccaaatat tacaggaaat 55920 gcataaatta ctttagatag ctctttcctt cagcaaataa aagctagtat tcctaagttg 55980 agttgactgg caaacacttt aataatttat gtttttgaag cacaaaaagg aaaaattaag 56040 tggcaatctt caccaaaaat gacctttgta atcatataac acacaaaatg tactggaagt 56100 tttcaatagt tcatggtttt gatatagaat agatggataa acaatacatg tactacttag 56160 atcctggaag aggaaaagct ggagacattt ttgagttgtt aaattatttc ttgcagtgat 56220 gatgactaag aaggataaaa gagatccaca attttatttt aatcttctac agtaagggaa 56280 attgtaataa tatctcaaaa agtatgttct taatctatga gctacttctg gatcctgaaa 56340 aattataaat attgctgttg acttttcaag tagtgctgta ggcctatgcc tttctcagtt 56400 tttgtgagca cattaagggt gattattttt ggcaaaaaag tagagtatag ccagctaaat 56460 ataattgcga ttttgcaggg gccaggaagc atgaaggatg gttgaaagac tgctatacac 56520 aattaaatgt aaacagtttt tcaagcagaa aatttgaaga ctaaacacat ttaccttcca 56580 atatgcttac caagtttcct actgtaagca cattattgaa atggtccgtc attggatagt 56640 gctccatggc catgaaaaga gtatttaaga caatacagat ggtgatggcc aggtcaacaa 56700 atgggtccat cacaaccagg ttgacaacat gtttcacttt taaccaatat ggagaacagt 56760 cccagattaa gaatatgttg gaaaatttat accaacaggg tgggcatttc tgcctggatt 56820 cttcaagttc tagattaaga aaaaaaaaaa aaagaaccac caaaaggtat actttataca 56880 cacacattta tttcatatcc actaaactta ttttcagtaa tcaacacatt tttgttacag 56940 agacaacctt ttttgtactt gttaaaaaaa ttacagttta ctctaaacct cccaaggata 57000 tttcatcaga cacacacata gagcccaggt aacaatgggt agttttttgt cttatgcact 57060 gacattgtgg ctcagcactt ggcctcaagt taaatgagtg gtctttcatg tgacgtctca 57120 atgggaacat ggtttagggt ggtgtagata ttgtgtgtgc aaccctatgt gaatgactct 57180 acattgtcaa cctcagacta tgagagctag aatagggatt gatgtgaccc aagaatcatc 57240 tttttagctt gtttttattt tgtgaaaatg acctgctctt cctctacaat cttgagagta 57300 cttaggatga ggctgaaaag ggctgtactg ctgaagtctt aaactaatgg aacaaaaaga 57360 gggtcactat gactaatgag attagaaacc cctaacagaa atgctttgtt ctgcattttc 57420 aaagagttgc tacacagtta ggaaaacatt cttagtccca atatcactca ttttaaaata 57480 aattgttaag gcttctagaa tatctgagta gatataagaa ataacagctc ttgaattaga 57540 ctgtcttttc attagaatgc actattccca actcacaaat atatttgttt gaaatgagac 57600 aatataagtt tggtgaaaat aattgaaacg aaaatagaat ttgttaccaa ccttctactg 57660 tatttgttag aatgctggct atactcattg ctcgttgcct ttgggaagga tcttctagaa 57720 agtccatgga aacgtggaaa gaacttgacc ttctctttct catttcagtt tcagtggttg 57780 ttccctgtaa aaaaaaatgc taatgcatta aacaattaat ttgagcaata tgacaagcaa 57840 acaaccaaat ggtgacacag tgaatttcat gaaacacatg catcatgcac tttcatattc 57900 aattggtgat ggcagatatt tctgacttat tgtatcatta gcctggaatg ttcaaactgt 57960 taaccattta gtcatacagc aaaaaccaag atgttaactt cctgatttca taattttata 58020 aaatacaaaa taattttaat atagttgata aaactcttaa gagatatatt taacagttat 58080 tacccttatt tctgaactaa tagtaaaagc ctagtaactt aaaagtccta caagtgatca 58140 aggcacttga tttttgagaa ggtagctatt taattttaag gaagtataaa tgattgcaac 58200 acacttagct gccatcttat tttctggaca caagatgtag atggtcattg acaacacaaa 58260 ctctatgtta aaaagaacac acacatgctg catggacaac agtttcatcc agggtaccaa 58320 agcaataagt catctaattc tgacttagtc atgcctcctc atgctgatat atttccaagt 58380 gagtaaacag tctaagaaga ggcagcatct gtttagaaat tcctcatctg agtatacatc 58440 cacaaacaca taacatacct ttgtacacag acaattattt tatctgtctg tattaataat 58500 gtatttgtgt ctcttcattt aattttgaga agacctatat cagcattttt tagtaagaaa 58560 aatatgagta ctaggagtat taaggtaaca atgaagctat ctacttaagc agtgtttttg 58620 aaaatctaaa ctaaagcaga gatcttgaag aatccattgg aaagatttat tacataccct 58680 tgacacttaa acatagaatc attcatttac tttcatacca gagccttgga gaatgtcctg 58740 ctatctaaat tcagtgtggg tatatagcaa atcctccaac tggaggcagt aattattgtg 58800 tctaatcaat ccttagcact tttaataagt aaatgcattc aggtttgtgc aggagactgc 58860 taaggtttta agttttagtt ggttagtcta ttaaagatat tacaagatgc aggtgcattc 58920 acagcgtgac caaccaggaa tcattctcaa ggttgccgtt ctgtagaaac actggctggt 58980 gcagcaatag tgagccagcc atgcctgaac tatttaaaac ttccttacat tgtcatcagt 59040 agctggctta tctattatca cctctggcag aagctgtcca acaggcgatg taggaactga 59100 aggtccacca accaaggaaa ccacaccatt gcaatccaca gtgctgtgca tcttcccatt 59160 cgctggaaac actgccagca tccgggatga cctactggtc tgactcaggt tgctgttgcg 59220 tctctctccg tgtcgtcggg gcacaaacaa ggaatctcta cggctctcgt tatcctcaaa 59280 ggtgctgtgc tcatcatctg cgaagtcgtt ctcagatccc acatcctttg ctcgccctct 59340 aaagctgaaa aggcttgttc tgctatttcg ccttggtgaa aatagggagc cacggatgct 59400 caacaaagac tagaagtttg aaagagcaaa caaataaagt catattaata tggacatttg 59460 aatgtgattt cattttgcaa gattatgtag aaggagattt cagcattcat aacagaatat 59520 ggttcattcc ttttgattat cattctcatt ttatgtgcat tcacattaaa ttaaattacc 59580 ttgataaaag aaagtttcta gcccttggga ttaaagaatg aggagataga ttgcaacctt 59640 aacatattga aacacacaca cacacacata cacacacacc ctgaacgacc atttctcaag 59700 ttcaaaggga aacatcctta gaatatggca atggacgtgg taaacattca gtgaacactg 59760 gcaccatgac cttaacaagg ccaccttggt ttttatggat cttgtctttc aaaaactttc 59820 aacactcctc acaatttact ttagtccacc tttctaaaat cactttaatt attatttctt 59880 tttcacctat aaggcattgt attgttggaa cttgaagttc atacttctga aattcagagt 59940 catgtgcctt ttgatcaagt gtaccatgac taatattttc agaagcatgc atggtgactt 60000 ataaagaagt tagggggaaa aaaaacataa aatcataaaa taacctaagg acattcctga 60060 tcgactatcc ggagttccac attttttttt ttcttaaaag tgctgaggat caaaaagatt 60120 aaatgtcatt agttatagac aaatatcagc agacagtatc agaatgacag tccagttctc 60180 ctgactgtca acttggtgtt atcttaacta caccgagctg tagacttaca tatctgtgga 60240 gtaaagtttt tgcataacta tgtgaagaag ggatgggttt aaatataaca caacagtggt 60300 tgattcagtt gataaaaatt cctgagtcca ttttctaatt ctccccctct ctcccatgtt 60360 ttaattttca accatgcatc agtaaactca gcagtgccat acctggtgtg gggaggagta 60420 cctcttttca tatgtcaatc ggttcccttc aatggagaag cgaaaacctt tcctcctgat 60480 gctgtcctca gattcagatt tttggaattc atcctcatct ttctcttccc caccagactg 60540 ctctttctgt tttcttttct tcctccgatt tcttctttcc ttagcactct tggaactcaa 60600 cttagaggct tcagatgagc tgtctgagag cctgcctgct gcactgggct ctctggaatg 60660 ttctgaggca gttgccgttg ctgcctgcta tattgaagag aaatgatttt aacatagcac 60720 ctgaagagac tgtatctttc tttgaaaggg ctgaagtatt tgcatggctt ttaaaaaata 60780 tattgaactg actgaagatc atctcacaga gaagattctc tgcaagtata agaggagatt 60840 ttttttttct ttctacctaa tgaaggcttt tggagataat ttagtttgct ccatggtaac 60900 atttattatg tctctgttaa tgctccacag accacgtatt caaaaatatc caacatgtat 60960 caacaagaaa ataaattcat tactttttgg gatttgattt actttaaaaa ttggtattta 61020 attagtgttg ttttcttttc tccgaaaaag aaactcgagt atggaagaaa agctgatgag 61080 tttaaggcag gggaatggga taaggacctg aggtcctttc tctagttatt gaaattggat 61140 tgtccaatac cctcaaaata ttattaatcc tatttatgga cagttataaa atccctttct 61200 cacccatcca caatatccag aagaatgggg aagggagaat caatagtttc tgctgagcaa 61260 gataagacat ccagttctcc aaaaactgtc cccaccatct tcaaatcagt actggttctt 61320 aaggggcaca tgggcatgga ataaaacaat gctttttgat tatagcttgt actggtacta 61380 agttgacact tttttattat tatcattgtt cccagggtaa cctcgataaa ttaattactc 61440 ttgcatataa attaatattt ctgaaacaac tttcttcttt agtaaagaca ataagtttgt 61500 atgctaaaca gaaagatgag agagatagga gaggcatttt atgatttatc acactgtgag 61560 gactaacact tcactataaa aacaagtaat cctttttaga tggtcaatct gtgtaagatt 61620 ggtaacattc atatgtctat tggatgctgc tgtatcagag atcattatat tatttgatca 61680 cttccttata aaggtaataa agcaaccacg ttaaaagcca acatattttt agttaaagaa 61740 aaaaggagac tatgtttaag aactagagga gcaactcttc atatgataac caataatttc 61800 ttgttctaag aaaagatgat ttcctcctaa tgccagtcta ctcattgaat aaaagtctct 61860 cacttgaaaa taccccaaaa taacattttc cctttacttt gagaatctta agatgattaa 61920 aatagcatga gagagttcta ttgtggttat tattatacac atctcaaata aaataattaa 61980 actaaataaa agtaagtgga tcatcaaaat atagaaatca ttattaattc ctcatacaac 62040 cacctgctct taggtactca ctttctcttc aatattacgt aacaatcaga acgataaaag 62100 gtcagtgcca tgagacaggg cagctttacc tgagctgcct cctgttgctt tttaagctgt 62160 tcaatcatct gctgaaattc ggcctctttc tgttctgctt cttccaaggt ggcctgattc 62220 tgttcctcgt aggccatggc caccacagcc aggatcaaat ttattaggta gaatgagccc 62280 aagaaaatga ccaatacaaa aaatatcatg tacgttttcc cagcagcacg taatgtctgc 62340 aaacaaaaat atcagaatta tttctcaata ttatttcact aagtggtggc ttcaactttc 62400 aatttactca tgtgtctagc aaaactcaga tataaatagt aattatgttg gtcatagcac 62460 cctgtacttt ttttttattg tttctttaac ttcagcttct tccttctctt ctagcttatg 62520 cattcacact atgatttcta tggcagaatt tttgtattca ccaagaatga aacagtcaat 62580 aaaatgccat ggagtcctcc attaacgacc tgagccttta ggaaagtcaa ggaacagacc 62640 aaagttatct ttctatatct gctttttcat tttcattact tcccacctga gggataatat 62700 ttgagggggt agatagggct gaagggagaa tgtgccttct gtttaggaca atctgtgtct 62760 gagaagggta gggaacaggt tttgagccaa gaagaaatgg gagagaattg caatccttgg 62820 catcactctg ctcagtatgt gttataatca ataggataga ggaactcaag tctcgtttca 62880 agttctgctc tttctactat attatcatcc ggttttaatt tcataactca attggttttc 62940 ttgtatactt ttacttaaat ggagagtgtg gctctttagt tctcaccagt tgataaagat 63000 tttcccagaa gtcctgagtc attagtcgaa acaaggacaa aaaagcccaa ctgaaggtat 63060 caaagcttgt gtagccataa ttgggatttc taccagcttt cacacacata tatccctctg 63120 gacattggct gcaagtgggg taaaagaaag tattacaagt cgttctgctg cctttttact 63180 ctgatactat gctatgatat tgcctagtca gaaagatttg gtatttcaaa ataaaagttt 63240 gacaaataag taactaatct atttcccaac ttttgactgc atatagtctt attagctact 63300 tggtgtcatc attaaaatat ggtgcagcat ttctaataat attttacaaa ataatttttg 63360 ttgataattt gcattttcaa cacctccatt tcatttttac tactatggag tctccagagt 63420 ttatagctca atatacttat ctaaaagaac aacattgtta ttattatata ctcctaaaaa 63480 agtaggaaca ggattactcc tctttttgta tgtttgctgt tatatacagt aggtgtttaa 63540 tagatatttt tctctttttt tatactttta tttgaagttc aggggtacgt acatgtacag 63600 gtttgttata taggtaaatg tgtgtcatga gggtttgttg tgtagattat ttcatcactg 63660 aggtattaag cctagtaccc actagttatt tttcctgatc ctctccctct tcccaccttg 63720 cacactctgg taggccctag tgtgtgttgt tccctatatg tgtccatgtg ttctcatcat 63780 ttagctccca cttataagtg aggacatgcg gtacttagtt ttctgttcct gcaatagttt 63840 gctaaggata atagcctcca gttctatcca tatccctgca aaggacatga tctagttatt 63900 ttttatggct gcatagtatc ccatgatgta tatgtaccac attttcttta tccagcctat 63960 cattgatgga catttaggtt gattccatgt ctttgctatt gtgaatagtg ctgcaatgaa 64020 catacgtgtg catgtgtcta aaagtattac ttcttgtttt agaaaacata aatcttacct 64080 aatatttaca taatctcata ctttatcaaa aaccttacat atagcaaatt aatgtcaata 64140 aaattagttg gctgttatct tcagtttcta taaaaagaga gaaaagatac acatatgtat 64200 gtgtacatac aaatatacac agatacacac aaattattga cttaccctgc atcagagcta 64260 tttccacata gtagtgcatc taaaaaaccc tccaggaaat aatgatatcc tgtttgaaaa 64320 aagaaagtcg tatgatgaac atttgcattg ttaaaaacac tcaaatgaga acaggaaggt 64380 caggttctac ttttaagttt attgagtaat tttaaatata ttattcattc aaaggcacaa 64440 gtatttgtct cttctccctc taaattctag atattctatt agatacttta cagtgcaaag 64500 tatttcttca ttatgaagaa atgacattag attagataca gtgcaaagat actttagaca 64560 ctttacagtg caaagtattt cttcattatg aatgtaaagt tagtgataat gacaggtact 64620 aacataatct ttcaaaaagg tattagcatt tgttcaccat tctcacgaaa aaaattcatt 64680 cagtaaaaat agacaggaat gacaggaatt tctttgtttt tgcaaaacag ccacatattt 64740 caaaataaaa gaatagtata ttttctggtc ctctcgccta tatttttaac actatacatt 64800 ttaataatta agtataacat attctcacat tttgcagaat ataggcaact tatagtaaaa 64860 tatgcataaa tcatatcaac aactgaaatg aaagcaattt taaaaagtct taaatactaa 64920 agctaaaata atgactatag gtgaacacta cattatctca aagattcctg tttcttgcaa 64980 actccttggc ttcttgcaat gtccagttct tctataactt tttccttggt attttcaact 65040 ttctttctac taaatattga cataattaag aactcccctc actgtgctac cagtaacctg 65100 tatatacttg aattattctt aggatgacac tactatattg taattattta tttacaaata 65160 ttcctcctag aaagtcccaa tcattaatta tttctatatt agtgtttgtt tgagaccggg 65220 tagcctttct gtaaagttta ttgaatgaat aagtaaataa aagacaaaaa gagaaaaaca 65280 tggaattaaa caatcaatgt tggattttgt aagaagatat attttctaga tgctaagttt 65340 tctgaggaat ttattccata catagttctg tacaggacac agaagcacat aaggaaaaat 65400 atcattttta tttctaatat tctgacttcc ttgaacctag acaggaaagt tgacatagta 65460 tttcctaact ttcaattaaa attaaacaaa gagaaaggac tataatagtt tctggatgaa 65520 tttttgatat ctcatattta taaatgaagt tttgcccatt aaattcaatg atctaacctt 65580 aatgatcagc cttaacctga ggaaaatata atttttcagt tataatagtt acctttaatt 65640 ttaataaatt taattttcta ttattttcag aaatgaacca ttttatttat atttgcattt 65700 ggtttaaaat aagaaccata gatgtttaga gctgaaaatg acctcagata ttattttact 65760 tcgagtattg gaaaaatgca gtccaataaa ttttccctag agagaataaa ccctaaataa 65820 ccctcatagt cagtattttg aacttagata aaacaaacaa acaacagatt tcagggagct 65880 ggtgattgaa gtggacctac tggcattcgt atcaccagct actaaggagg ctgagatggg 65940 aagatgccac cacacccaac tcattaaaaa aagtatatat atatatatat atatatatgt 66000 gtgtatatat tttttttttg tagagaaggg gtctcactat gttgcccaca ctggtctcaa 66060 actcctggcc tcaagtgatc ctccagcctc agcctcccaa agtgctagga ttataggtgt 66120 gagccactgc acccaactaa cattttctat tactgtctcc tgaagcttta ttaactgtaa 66180 ttttcttctt tttaatgtaa tactactttt taaatataag aataagattt acttttaggt 66240 atcactttat ttccttaagg taataaaata atctattaaa ctataacact ctgaagccat 66300 gcattacctc cattattttc cccagtgtac tatacagttt ctgatacatt aaagacattg 66360 tgtaattaat gtataatgag ttacatttgc atagtattgt agaattcgca aagggcattc 66420 acatatttta tctcctttca ttatatcaat caccacagga agaatgtata gcaaccaagg 66480 atcctaggaa aattctttct agctgaattc ttcagccttc caaatgatga taaaatagaa 66540 agtggcattt aggagtcaaa actagagtag ttatgaacaa agttgttaaa tgtatgtgga 66600 agccattgat aaggtgatta acaaaattct tcttttagtt ccagaaatat aaataatcta 66660 ttatttaaaa tccagggggt agaaatacca aataaaatat aattttaaat attgttaaat 66720 agtttgatta ggtaattttc taaaagatca cgtcttgtta tgtaatcatt taaaaatatt 66780 tttcattcct agatggaagg cacattagca atgaaaagac caaatataca tgatagtaat 66840 tcttttttag agggtgtttt atttatttca ttagttttaa attttaaatt ttaatttttg 66900 tgggtacatg gtaggtgttt ctatatatgg ggtacatgag atgttttgat acaggcctgc 66960 aatgtgtgct aatcacatca tgtaaaatgg gatatccagc ccctcaagta tttatccttt 67020 gtgttacaaa caatccaatt ctacttttta aggaaatgta cataacaata attcttactt 67080 gaatcttgaa tatatgactt ccagtcaaac tcaaagacag tttcatttat aagtgtacca 67140 ttataattca cagttatatt cttttctata ctatgttcct ccaaggaagc attggtggga 67200 ggccattgta tacatttatt cctcaggttg cccatgaaca gctgcagccc aattagagca 67260 aatacgctca gacagaacac agtcaggatc attacatctg agagcttctt cacagactgg 67320 atcagggctc ccacaatggt tttcaggcct gaaagaaaga agtctattac tatgaagact 67380 taacacgtgt gaaataataa aagcttcaca caattttctt gaaaacatag atttcattca 67440 taaatccaag aatgtttgca acgctagtgg agaagcaaca cttcattgaa ggggaagaac 67500 ttatgaagat aaactccaga aatgtaatga tttaaacaat gaaatgaaga ttcatatccc 67560 attatgtcga gatagagtaa tggaaggttc atgttcttca tggagcctat attaaggaaa 67620 gggccttgtc tttttccttt ttgctactga aacttgtctc atattttcat tagggtcaga 67680 ggtcagtttt ataacaaaat acctgaataa atattttaaa attcctattt ataagtagga 67740 aagattttgc tgtacaaccg aaaatggtct gcagtataat tgtgccttaa gataataaat 67800 cctccatgca gactcacact attctttatt gtcttattcc cttctctttt gttagcaaaa 67860 aacttagaag atttgcattg tatacacata gtcattaatg actctaatga ataagaaatt 67920 acagattggt acatttaaaa gggagcaaat tctcgataaa actaacatgg tgaaaaaaaa 67980 aaaaacccat gatatttgta agtgcaggtc accttgacct caaattacag tatctcacat 68040 aagacattgt taaactccaa ggctgataaa gcttatgtct aaacaataag aatcattttc 68100 tttgaaacac ctagtcttat gattcctgat tttctgtaaa actgaatgtc aagcagagaa 68160 ggatgctgaa tcacatgatg ggtccgtctc attatctaac cttgctctca cctggaatga 68220 ctgaaatcgt cttcaatgct cggagaactc tgaatgttct caatgccgag acattgccca 68280 ggtccacaaa ctctgtgacg tacctgtaat agggagttca cacacaaaca caaaaacagg 68340 acacaaagaa aaagctgtag gtacaaagag cctatccttt actctaatca cttcttacct 68400 ggaattaccg aaatagtttt caaagctctc aagactctga aagtgcgaag agctgaaaaa 68460 ttgcctaggt ttacaaattc tgttacaaac ctgtagaatt aaatcagaat tattcaagat 68520 tttagcagga tttatattac ttgcatgggt cttttataaa gaccttcttg gtgattttaa 68580 atgataaata ttataagtgg taaatcagga attagattcc atcattaatc tttgttcaca 68640 taatttaagg ccattagcta aatgtaaact tcataaagta gacacccttg ttgtcactct 68700 ggaaagcaat gcaaccaaca tcatgtgtaa cttgtaaaaa gaaagtaaat cttggctatg 68760 gtttagggtt ttagttagaa aaaaatatat gaaatcaccc aacagaaatt taggcatgaa 68820 aaggcagttt gccttactgc ttttatatat gagataagat tttcctagtg taacttttaa 68880 ataaaagtta agcaaattaa gaacaatact tgatgagggt ccaatgctgc gcctattgtt 68940 actgccattt tgttcttaag aaatagaagt cctgtaggcc ttcttttgag ctgtgaccag 69000 agagcctagc aaagaattgg ctcatcctga tcagatagga aattaagacc agacattcgg 69060 agtcctgagt gtatcagtgc cacctctcct gctcctatcc actacatcac aactgttaga 69120 ggccaaaaaa tcagctcctg aaggaaggat gagggtaagt gttgttgggc tgcctccttc 69180 tacactctac tttcacttag tctggaatgg ttttctatta tttttctggg tctcttcctg 69240 aggaagtttg ccactagaaa aaaaagcatt ggggtgcata aactgtgcat attactgagt 69300 ggatatgaat aggagataag gataaggaag tttatgttca gactaaagag atgaagagag 69360 ccataaaagg aaagaagaaa agaagaaaga aaaggggtca ggagagaaac agaaagaggc 69420 agagagaatg tattcctcta caggtcttag aaatcagtaa tttaatatat taaaaacata 69480 atatttcaag tatcttcttt cttctcttag tttgatttgt cagatcgttt tgatgctagt 69540 agatacttac tttcaattat tttaccaaac caataaaaga agctgtgtgt aatatcagca 69600 aggtcattgc aaatttgtgt agccaataga actgttttgt ggctgtaatt tttaaagtta 69660 ttttcacaga tgtattacaa atatgcttgt gttttgacat tagattgtgt gtgttcatat 69720 gtgtgtgtgt ttgtgcatgt gtgtgtggaa gagtggcata tgtgaaattt tctgactgat 69780 gctacgtgtg aaaattgtag ttttcaacta ctgcaaagcc ttcatgctat agtgaaattc 69840 cacttagacc tttgttgtgc taaattgaaa tccagagttt gaatgtataa atcacaccaa 69900 aatattctac aggtaaagca aacctattct taaaagcata agcactgatg gaaaaccaaa 69960 ctatgttctc tcttaaagtt tcaaaaaagg cacttacgca aatgtaatga cagtgaaatc 70020 gagccagttc catggatccc gaaggaaagt aaaatcttct aaacagaatc cccttgcaat 70080 aatttttata agtgattcaa aagtatatat tcctgtgaag gtgtatctga aaacaagcat 70140 ccaaaaaatt tgataaagta acagtgtttt ttcatagcat accaatttct tatcactcca 70200 tcagtggaat agataaatac taaaaaagaa aactaagcag atggatttta atttcataca 70260 aatgaaacgt agccctaaat ttaaattcag cttcctaaca caaagagttg tttcgtaaag 70320 tgtcttaaga gtagtgtgag aaatacaagg tatatgaaat ctatttagcc attgtctgaa 70380 atgtcttggt atttatgtaa atatagtctc ctgagaaata tttagtatgt ttacatgatg 70440 gaatagccaa tcaataatat tgcagaagca tgaaatgatt ttcttttagg gaaaaaaatc 70500 tcaagtttaa tagtgttcta agaatgagag gaaactgaca aattagcacg tgtttttttt 70560 tttctacaag ataatttaac ttgcttggaa caaggacttc tttaaaatca aagtaaatac 70620 ttctagggtt ataagaagta aaaatttaat ttagaataaa attcttctga taattcagaa 70680 acttaggtgt ttccaaagtt taaatcttct actcagaaat tggggtgtga gagtggcata 70740 aaatcacaag aaaactaggg cgactgaaaa cctgtggggc ctcccatatt agcttcaata 70800 ctttagaatt tttttgtata taaaatttat tattttcttc aagatgtcat gtttcttatt 70860 ggtttcagcc tggaagtgtc taggaaagga gacactcttg gaaataggtt ggtgcaaatg 70920 ttggtggaca ctcttggaaa taggttggtg caaacattag cttcaattga aggtaatggc 70980 aaaaaccaca attatgttta caccaaccta atacttctgt agttgctatg ggtcagcagc 71040 tgtatagtaa caggcattac aaataggaag tgtgggcagg tgagcagcta tggttagagt 71100 agcccaactt cagttatcac aaatctggcc tctgtgcttc gaaggtatcc ccagaacaga 71160 gagatcatca atatagttag taatgcttct ggtttctgaa agctctacaa aaagttccac 71220 ttctgttagt ttagtcttca gtctactgaa ttttcaagtt ctacaaccct gaaactttgg 71280 attatttttc aatttgttgg tgaccacgct tggaactata ttggcctgac atgaagtgaa 71340 tgtgcctgat ggaaatgaaa actttgcgag gttcaatgtt gtcttcacat ggcatttgta 71400 actaaccctt tttgattctt gattcaatgt atttatctgg aatttaactg gaaccaatgt 71460 ctaccatatt ggctcttttc tgcaattgct ttgaccacat ttggtttggc tactgtagat 71520 tttaaagaaa aaggggtaaa tgtccaagag tggtggtctt caggtgaaca ccaggtacag 71580 gcaaaagaga gtgataatca gtataacgcc agcaggcctg agggccaatg agcattgtcc 71640 tcttgctgcg taattttgtc taggaatgac tttaataaaa tgctcttcag ttttatttta 71700 agactacatt aagacacagt ttcaaaatcc caaatgtata tatgttatta aaaatataag 71760 ttgaacttac tctacattct ttgtccaatc aggagggtta ctcattgtca taaacacaca 71820 gtttgtcaaa atagtgcaca taattagcat gctgaataat gtaggttatt gttaaggaac 71880 acacaaaaga aaatcaaaat ccaagtgtta tattacaaaa agctaacatt gaaaagccca 71940 aactgcagct tagccaaaat tcagggataa atgcattgtg ggcaagtctt ctaatctcct 72000 tacatttcaa tttcttcatg tgtaaaatgt gggtaataat atcaccttca ctgagtattt 72060 gtatagatta aatgaggtaa tgtatatgaa agcattatat cagtataagg tgttgttttt 72120 acaactatta ttaaatcaat atattcacct cccagagaac ttcagtggga agactatttt 72180 tgtgctacct ggagttgcac agtttttcag cagaaagtat tgacttgagc tcattcaggt 72240 gaataaacta gtaaattgtt gaggaaggcc acttatctgc aatattgtaa tttcttaaac 72300 acatcttatc caacacagtt caacgcatga aaacaatttg tagtcaaagt acagcacgat 72360 gctaattgtt gggttgctct attttgactg agtttataca agtgcagcag gattcgataa 72420 cattaaaagt gaatattctt gaaggttgac acttaacatg atgggaatgt aattaaaatt 72480 caacatagca aagtgatgtt ggccaagaga ctcaacctct ctgtgccatt gccttgtatc 72540 tcttcctact tctctacaat ggagctaata atgtactcat tttgtaatgt aaccatttct 72600 acatgcagat taaatgagtt aatgtattgg aaatgcttgg aacagtcacg gtacgtaagt 72660 aaatatactc taagtggtag ctaaaacaaa tgaacagaca taacagaatt ataaaactga 72720 aagggaccct aaaaattagt ttatcactat attttaaaaa tcagggaaat aaggccttac 72780 taagctctag aggaatcaga taaagggtcc aggactagaa tataagtttc ctacattaag 72840 atccaatatt ctttccacta tagtttactg ccaaaacaaa aattttccat aattgaaaaa 72900 gaaagttttc atcaaatgac cacatgatgg cgctaggaat acaaactggg acaaggaaac 72960 ttccctaagt ataaaaaccc tatcatatga tttttatgtt tcaaatcttt taattttagt 73020 aatagcatat ttataccact aaagaaattt cttgctgtca tattaaaatt agaatggccg 73080 ttcaaatttt agaatccttt aaaaaaaagt atgagcttat gataattata atggtatttt 73140 aatatctatt attgtcaaag ctatcaaaca agatacaatc agaagtgaat tgttttccta 73200 aattgattaa caaatgaatt tagtcgtgga gtccttttta acaccaatgg gaatcatgaa 73260 accaaatccc ttaagaccat ttggaaatat atgccaactt ctctcattaa cttccggagt 73320 ctttactaag caaacagttt tgcatggcag catcataact catgacttga atttgaaatt 73380 cagccaatat tccagtactt ccttcacaaa aatcatcagg aaatttcaag aattaactaa 73440 gtactggcca aagactcctg acattctctg acagaaaata tacttaaagg tttattctaa 73500 gatacactga agtgttttat atcataacta tggataaact tgagtctgga agtagatttt 73560 tctgttatca tatcattgct cactgaaaat tctacaccat cacaaacttt gtataaagat 73620 ggtagaggta aacatggtta tcttacttta gatttgtagg attcaataca tataagtgtt 73680 tttagaaaga taacaaaagt acataaatac atgtttatat ataatatata aaatgttaaa 73740 gagtacatgt ttcagtaatg tctatgtgat taatgaactt taagaatgag gctaatatga 73800 caaagatgca aaatgagagt gatgaaaact atataatatg gacatttccc aacttaattt 73860 gatatttagc tataaagtgc ttacagatca tgtacaaata gttaatatta atcacttgaa 73920 aaaggatatg aatgtaccaa aatcttaata gctattttcc taagaggatt gaagggagtt 73980 aaaatgtaca gggcagaggt ggcactgaac cggaagatgg ccttcccttt attcaatact 74040 ataaaagtct gtaagacagg aacacaacat agaagtatga aagtataaac cacttaaact 74100 ctgttatcta ctttctgtta cttgtcataa taaattattg taaagttaaa tgagaaacca 74160 gcacaatcac aatttctaaa gtgccccatg aaaacaaact gtcactggat ctcttcttaa 74220 ttagagagga aatccaatga taccacttac cttttaccta atacttaccc tcaattttat 74280 tgtacataag acaattagcc aagagaagtc atttattttc tcgatatttt aagtgtctga 74340 gttaaatgaa agtcttaaat gggtgcacat ttcatttcat tccaaaaaac ttaaggcact 74400 acatgctttt tatagtcatt tcagctttcc caattcaaat atcttgaaaa ttaatcctgt 74460 ggaacgcaaa atcattcaac agaactgata ctatttttga aataaagatt gtttttacca 74520 tctatcctca taaaataaac attatcactc tcttcgtaat agaaaataaa aacagccacc 74580 atcaaaccca ctcttgggtt agatggatgt aatccaataa ttgatttctg gaggccaaga 74640 tccctggaga gtacccgttg accaggagtg ctaaattctg tactgggatt tctgagttag 74700 ctgacatatt gaattctaat cccaattgac ttcctatctt atgcagtgct ttcttatcac 74760 agaggagaag ctccaagctc ctgaagaatc caggatccat gaatgtgaat gaaattcctt 74820 ccaaaaatta gacttatttg agatcaattg gcagtgggca gacaaaacat taaagaagca 74880 acatgtaagg gtataaaaag ggctctgact caatgttttc caaggtgctt acttatattt 74940 agacagagcc agggagaaag cctttatctc tgtgaagagc atatttgggg aaggaaattt 75000 taagcttctt gattttaaat tcacccattc ttcgaaagct ttcttttcta agccttagga 75060 tgcatatctg cacagatcat gttatgatac agcaagcata aatgttatgt ttattttcta 75120 ctaagaatct ttgtatagtc ttagctcatt aacagatttc ccctatactt gcaggatttt 75180 ctaaattcaa gtaaagcaaa cccaccctcc cacaccccta cctgctaatg gagttggttt 75240 ttgaaaatta agcactttct atctggtatg ggtagaagtg tcctaaactg gctgtgaaag 75300 tatggtcccc caaccagtac tggttaagta tagatatgga gagtccatgt ttagaaattt 75360 gtaaggcaat ttggccaatt aatgttgtgt ctgtctattc taataataaa aaagtagggg 75420 gatgttgttg tgggcctgtt tttcatttca gttttctaga aactaatttt tacttcattt 75480 tatagaagaa tagagacctc acatcctcaa cagagtttga gaagcactgc tccaagtctc 75540 acctctgcct gcattccctc tatcatcttt gaaggagtat gagtccagaa aacagataga 75600 gctttaccac aaagcgcatt tgaaggaagg gagaatttca cctgtgctta ctagaagaac 75660 aatcccctat gccaacaata cttagccctc tttttctctg attcattgag ggattctgtc 75720 cctgaatgac attgtgagat catcgtaaat ctgaacagac ttgtgcaatg caaatgcctt 75780 tgctgtgggg gaatatgagc atgtaacgac acagaaaggc ccaaagtgag ctagctcagg 75840 aataaatatg gtccaccttt caaatgtact gcatatactt cctttccccc cagatatgct 75900 gagtaaaatc tgaaagaaat attaggggct cagatggcca gtcgcagtgg ctcacgtctg 75960 taatcccagc actttgggag gccaaagtgg gcacatcacc tgaggtcaga agtttgagac 76020 cagcctggcc aacatggtga aaccccatct ctactaaaaa cacacaaaaa aattagctgg 76080 gcctggtggt gggtccctgt aatcccagtt gcttgggagg ctgaggcagg agaacaggag 76140 aatcgcttga acccaggagg cggaggttgc agtgagccaa gatcgcgcca ctgcactcca 76200 gcctgggtga tgagagcaaa actccatctg aaaaaaagaa aaagaaatat taggggcaca 76260 ggtaggagaa ccagtaaaaa tataacacag aatatatata ttttaaaata agaatctctt 76320 gatttcagat aatattaaaa gctaattttg aaacaaatag tagtgataca aagagataat 76380 gagaaagaaa tgacaatcca tagatggcct aaatcatggg ctggagtgtg aggataatca 76440 agatggtact gtttgtacct ccgtggataa ggaaaataac caggctcatc ctaaggagac 76500 aggaccatac ttagaagaga acacctgtga tgctggctcc ttggccactg ttcagcccaa 76560 accatgacca gaggtaataa atgaccaaaa cagaaaagac agacaaggag tggtaaagta 76620 aaaggcaaag ctagagatct aaaagaaggg aggggaaata tttctgccct gagtactaaa 76680 aagtaaaaga ggcaagattc agaaaccaaa cacaaaaggt tccaaaaagg aagtctgcct 76740 agaagtaaaa agagcagagg attctagaca aaaatcgggg aaaggtgggg acagagagaa 76800 atctgttaaa ggacacaaaa ttacaactag ataggaggaa cacattctag ctctccacac 76860 cactgtagga tgactacagt taaaaataat ttattatata gtttcaaata gctggaagga 76920 agatattgaa tgttcccaac acaaaaaatg ataaatgttt gagatgacgg atatgctaat 76980 tattctgatc tgatcactat acatcatatg tattaaaacc actatatgct tcataaatat 77040 gtacaattat tacgtgtcaa tttaaaaaat aagataaaag gaggtataaa gggctgaaac 77100 taagtaagat gagtttaatg aaaccaaagc actctcaatg ttggtatgtg attctaaatc 77160 taaaagtcct ttgacataga gaaaattaat actttgacac aaaagttaaa aacaaatggg 77220 cataattatc aattgttcaa gccttagatg aaaacattta ctgattttac agtgtattcc 77280 ctttattcat tttaaaaatt taaagaatgt gtagaagatt atttggtaac aagatttata 77340 tgtgcaatgg aaaatacttg caagttgaat ttataaatgg aattggtaag gtttttactg 77400 aacaacggta tttgttttgc tttaattttt cataagacat actgttgtgc aagacatcct 77460 tgctacccag gaagctaaca ataaggccaa cattaaagga ccattttttc ataggatttc 77520 ttctgtgaga actccatttt tctcagattg aaacatacat gcttatgtac aaacttcata 77580 gatgtagctt taaggtattg atggatttta aacagccttc caataaagca acagtaccca 77640 gacttgtata gcaacccaat atgtataatt ttaaatatga tagcactttc atgtcagagt 77700 aagttccatt tagaatgtca gtcttattat atgtaattga tcttatgttt gtttatttcc 77760 tcaactgtct gtatcttacc tccttgtaat tgcttacata gccaagaagc cgatcattca 77820 gtttataagt gttaagaatt aataaaagga tacttgtttc caaggactct cagatacagc 77880 tttctcccaa aagtggcatt gatgatattg aagggaggga agagtctgaa ggaaatactg 77940 tttgcttaca acaaatactt aagtagctct agagttttca aatatataaa tatttgcctt 78000 ccccgctata cgtataagaa agggctccaa gagggaagag ttcaaagact agctaagata 78060 ttgctgtacc ttaaactgta taaacaaata ttgtgtagct ttaagctaat caagatttat 78120 gaactattaa attgggtgac tttttaaaaa ctttttaaaa gaatgtattg gttagcttat 78180 tatagtgaag tatcttagca tcctttaaat ctaattagtt caacaaagat ttcattaata 78240 caacttatca ggataacttt tattgcatta agtcatttga ataaaaaaga aacagttcaa 78300 agttggtggt ggaggagaaa aggtttatac agtagtatct agcccaaaac aaaccccttt 78360 ttaccaccca aggctcatag gaacattgac atgactggct ccacttacaa gcagcaagac 78420 tttgtggttt agtacaattc aggcacatct atgactattc ttaatatttg tccttcagtt 78480 cattttagtg ccaaaacaaa tgctttaatt gcagttctac aaagaaatag aactgtttga 78540 aattaataac atcattttaa cacgtggata attttctgct tcaaaacaaa tgttgaagca 78600 tggcattgta actgaggtaa caactagatt ttatatatga aaaatcactt tacagactta 78660 tttgcaggaa tgtaacattc atacaatagg gttgttctag cttgtcactt atgtcttcat 78720 atacaggtac caagtttatt gggcatatat acaataagtt ggtaattatg tatgagcagg 78780 gacctagttt aggtccaatt gttaatttca attgatggca attcagaata catgtattaa 78840 ctgtttagta caatatttgc aatgccctgt gctacattct aaagagaaaa caaagataca 78900 taggttatga caccaagaca tttataaact aggagatgct caactatttg ttttaataga 78960 atatagaaga attgatgaag gttaccttga ccagcacttt ccaacagaaa tataatgtaa 79020 gctacaaatc tgagctacag ttatgatttt aaatttcctg agagccacat taaaagaaaa 79080 acaaagcagg tgaaattaat tttaacagta ttttctttaa cccaacatat ctgaattatt 79140 atcatttggg aatgaaattg atataaaaaa tttttgagat atgtatattt ttatactaag 79200 tcttagatct ttgaaatatg gagttacact tacatatttc aaatactcaa tagctacaca 79260 aggctaatta atctctgcta tattgggcag cacagaccta aacttaaacc atccattgtt 79320 cagcaagctc ataccttctt cagcaatcct tgccatgtaa aaatcatttc tggttttaaa 79380 gaaaaagcaa gaaggaagtt atatagaaaa attggtaata accctggtaa ttaacagttt 79440 aataatctgg gaagcaacat tatgaaaata taagtatgat ttgttttatc ttatgttaag 79500 ggtgcaaact ctgaaattag atttctgatt caaaagctaa ctttgctgcc ttccagcagt 79560 gtgatccgga acaggtttct taactttctg tgactcagtt atctcacttg aaaacagaat 79620 aaatgtactt agctcataga ggtaatgtga ttccaattta gctggtcaga ttttgatacc 79680 tagtttttat actttaaata agtaatccag atgattctgt catagcaggg ctgttaatat 79740 gtttgttacc taatggttgt aaaaaatcac aaaccattgg ccaaattatc aatgattatg 79800 ttgtacatgt ggattgaaat cttgcccctt gatctaactg aatagttact aagaaaataa 79860 ttatgttata atgatttggt agaaattgct atttatgaag ctatatttgt tattatctag 79920 taatcttttc ttgtttctgg gcttatagaa agtgatttgt ttacaatttt ttcccaggat 79980 ggacattgaa tttaacaagc catggttttc cagtttcttt ttctcattta aatatagcca 80040 ttaccttaac atttatttca atctaggggc catattcttc aaagtacata gtttaaacat 80100 aagctgtaac tttgtgtttc atctaaacat tattgaaaca ttgccaaata acaggactga 80160 ctccaaattt attgcacttt cctactctta aagtaaatct actggcaaaa acaagaaata 80220 acacaggaag gtgagctatg atgatgaaca atacacaaaa tgtagaatat actactggtt 80280 ggttaaattt atcctttagc ttcaaagttt gaaacaggca atttccaact tgtacatgag 80340 ctgtgctcca gaaatgcatt tggaagtcaa ttgtttggaa atgtgaacat atattctcac 80400 agatacacat atatttctag acccacaggt ctatcaaact gttaatgaag tacaattctg 80460 aatgaatggc actgagaaac tttatcacta tgtgtaagaa agtgttactc tgaaaatggc 80520 agagttctgt ccttgaaata gcctggaagt cagaccagga aaattatctg gctctagctc 80580 ctacccagaa gtgctattaa gtttttcata gctctaagct gctggcttgg aaagaggttc 80640 cagcatgaag ggggagaatt agagccatgt tgcaagagga gagatgcttc aaagttttgg 80700 gtgtgaagag cagcatagat ggtcaggaga ttccattagt ataatacata tctctgggga 80760 catttcttat gctgggtcaa ttccatggta tataatattt tttccccaag gactttaaat 80820 ggtctcacct acttcccttc tcatttgtca tagcctgtga gttcaagcca agcttttctt 80880 ccttttctgg ctcactgggg gatgaaaagt tttcttgcag gctttctacc tgactctgaa 80940 gagagtatgc catatttaat attttttcat ctcctagtct cattcaattt tttccttcca 81000 accagtgata accagactaa acaacaatct gtgtcacttg cctacccgtg ggccaccaag 81060 ctttaatata tagccttcac ttaatgacag atgtggtcct taagccacag attacaaact 81120 aaaatgccca cagaggctaa gtgacaatag gtacctgcca gttttaggca tataagtcag 81180 tgatgcctga actcatattt caagaggaat ccttagatgt ataattttat gagtgtgtga 81240 aagattttct gatttataaa tgccagaaaa taattcaaaa ttataaataa ttttgttagt 81300 ttaacaaaac atgtctgtgg actccatgcc tcacagtcag tttttaaaca ttgttgccat 81360 atgctcacac aaaagagaag aatttgtacc tagagaagag tctgtaaaat tgcttgttcc 81420 tatgctttag ctgggtggag ggttggggcc agtggaggag ataactctgc agaaggtgcc 81480 tccctagaaa gtgcctaggt aggcttttgt cagccaaggc tgcagagccc tcaacctctt 81540 ctccagcaga gagaagaaat tataacaaca aggaaaaaga ataaaatctg gagctgaaac 81600 atttttcagc cctatatcat cagaatgtac ataccatggg tctgctacac tattatatgg 81660 tcagttaatt tttctttgac tggaaagaac acttttgagc ccagcttgat tacaagcttg 81720 ctgtgtgaga actatgagca aactattccc ctcaatttct ccatctcaat ggagaagatt 81780 atactaatac caatcttagg attattttga ggataaagtg aaataaaaca tgtcaatgcc 81840 cttagtgaat tctaaagtgt caataaaaat ataaggatta aaatatttaa aatgcgtctc 81900 tgtattctaa ctcttaaata tacacatata agaacatttc tgtttctcca aagcatggcc 81960 aattttagta ttggaatttt caggttcagt atctttcttc tcaaacttcc tatctaagaa 82020 aatgaggcca tcagcttcct tctgtctgac acctaaacac ctccaaaacc aattctgact 82080 ctatccatta ttctccatct ccattgtcaa aatgctagat caagtataaa actcctaaat 82140 ttctccatag agaagttgag tgatttttaa caatgtaaag tggaccatgt tactgctgta 82200 cctaaatact tgttgggaat tcattttgct ttgaagataa ccttcaaact ctttaagatg 82260 tactgaaaga tcccctttat ctagccccag gtctacctcc ccaacctcac cttattctct 82320 tcttacctat tacaggtcag cttgattata tgtcttattc tatgctgttc tctttccttg 82380 gaagattctc ctctccctcc tcctttttaa ccttcagatc ccaatttaaa tgccatttcc 82440 ttatagaggc acacaattta aatttcctga attgatcctc tttgaaaata ggtgcttatc 82500 accctactgg aatttagtgg gaaaaaaaat ttctaattat tttagaagct aatctagatc 82560 actgagtgtc taagatttta gtttttcctt tgtcacctcc ctgtctctgt ctcagaaaca 82620 gtcccaagat ggtgatgttg ataaaaatga ataataataa taaataaata aggttttaca 82680 aaggcaggaa atggccaagt gttgaaatga ccagtaaggg ttcgggaaat actgccggcc 82740 tgggagacca gaatcacatc ttgcaaaatg gcatgagtag gaaacaggaa ggacagctat 82800 aggcttattt agattccatc actgacttct cttttttttt tttccactgc tgtgattagt 82860 gctatgactg caaatccaaa ctaacatggc aatgggccat ggaaactcac tggtctagtt 82920 ttaaaactag tcttaggcaa gttatttaaa ctcagtttta ttatttttaa ataaagacaa 82980 gagctatctt gaaagaatct gtggattaaa aaagaacagt aattatactg atattatata 83040 tagcatgtag agtacatagc tttttttttt ttttttgcct gcttaggaca ccttttctaa 83100 cagttcctct tctcttcctt ttggagtaaa tctctgcccc actgtcttcc catgtggctt 83160 ggtggagctg acccacccct tggcaacaca ggttagtata tgacagagac catcccatac 83220 caaggagacc atcacatacc actagccaaa gtgagtggtt cagaggaggc catgtgacct 83280 aattagactc aattctagga caactgctag agcttttgaa ggaaacctgg gccttttttc 83340 tttcttcttt cttgttttag cagaagatag tagttacaag gctgtaggat gttagtttag 83400 caccactggt ggctatttct gccatcttgt ggaagagcca gcctgcaaat gaagccagca 83460 tgggtgacag cagagctgac catggaaaag gagtaccctc atgacattgt ttgaggtact 83520 gggtattttg atattaaaac cagattcact agacacattt cctttatttt tccccaaaag 83580 ttgtttctgt tgggttttgg aaactttcag ttgaaggatc tcctatagat atggcagata 83640 ctctaaaaat gccaagcatc attttattga tcaacatcac catcttggga ctgtttctga 83700 gacagagaca gggaggtgac aaaggaaaaa gaagcacaag gaagaaatag tgcataggga 83760 agagaaagat tgggaagtca actacagggt cctggatgta agggagagtc tgggtgactt 83820 ttagttttac aggagctgat gataagcaaa gaacagctac acactgggga ctgcccatat 83880 gacaattcgt gaaattataa gcttttaata atcatcctct tttctgattt cccgttaatt 83940 acttttgcaa gaaaaactcc ataattccaa ttaaaaacaa aacaaactct ctccacccaa 84000 tttaacaact aaaaactcct ttggcagtga tagaccaaac atgaatttga aatcacaaat 84060 tcatatatga cttctcatgg agcccaagaa aaagggagtg tgcatctttt caggacagtt 84120 gatagcaaga gagaataagt tacttttaaa tgatccatag gactttttaa aaatgaatgc 84180 atttctgcac tccataatta acaaacatcc atttttacta cagatctaaa atgtctcatt 84240 ctatttccag taaactgtca cattgttaaa atgatatttt cttccatggt aataatgatt 84300 cgtctgtaat tttaacaaga acatgagaag gaagacattt tctgtaataa agagtgggta 84360 aagaatttga atgtagggcc aaatggtaca aaatcagccc aagctatgaa aggaaactgt 84420 gaaaaaaagt cccgtgaggg aaaaaaaggt gtgttcacaa gctaaaatgt gccttgctac 84480 acagctaaag taaataaaca aacaaaggga aaccaatctg gaatcatgtt ctaaagacca 84540 ctgagtcaga gctaacatga tatgaaaaat actgtcacca tattatgata gcattttttt 84600 cccctgagtt tttaacctgg aactctgaag gcttaaaaca tctgaggatc taaaaacctt 84660 ctaatgcttc tatgcatcag gaatgttcat gatgcataga tgctactatt tctttagtta 84720 ctactacaat attactgaac atggattaaa ctgctttaac aattttagta gaatatttga 84780 acattacata atttgcacat cttaaactgg gacaaagagg ataaaaatat gtgggcatat 84840 gccattggaa aatatactct cagcagtgac attttaataa gctcactgac actgcctttg 84900 taaaagatta cagagagctt cagtgtggtg gttgtgtttt ttctattcac ataaattcct 84960 tgcatgtaca ctactgcact ttaacataaa atataacata aggaatggat tctgcaaata 85020 tttttacaat tggcttgttt tgtctattcc atatagttga gaaagaaacc agagtctttg 85080 tatactgatg caaatgacac attaactatt gtactagagt ccaactttag ggaaatcact 85140 agtctaactg catattccat ttcactcagg caaatctaat ccacaccccc agtatcagca 85200 ttagtggaaa atctcgtcct aataaacatt ttccctggtg acatttccac tgtttgacca 85260 tttagctgtg tcaagagtac tgtgtatgtg taccgcattg ttttaatgaa gatcacccag 85320 ccaatctcag ataacccagt cactaaagta aaattagtca tcgaatattg aaagaaatat 85380 tcattatttt taaaaggttc agattttgct aagcattcca actttagtca gagcaaatta 85440 attccattta aggatatttt tcaatactga aataatccaa ttagaaaaga aaattaaagg 85500 cagaaaaaag tgtacaggca acttataaaa gtcttaagac ataaaaatgc agaagaagga 85560 aatttcaaac acataactca atcatgtgtt ctaagcacac catgttagtt tttaaggatt 85620 tcagccctgc aaaaagcttc gtgtgcattg ctgttgaatg acttacattt gaagatttgc 85680 ttgctgtcag ttcaatgtaa aagccatgag tataccttac cttggggaaa actctttcct 85740 gataacaata tttcccttat caggttgttc tacttgcaca ctgtgatttg ctccaaaatg 85800 ccaaaatgct tttctttcct cataccatgt gcatttgaag ataagaacag aagatgttaa 85860 gagcaagttt agacgtgagc ctaacaaagt ttataagggt ttcctcgaca caagaatctg 85920 gctgtcactt catcagagtt ggcctttcac cctcagtttt aagatgtttc ttttgagtat 85980 tttgaaaatg tttgcacaat tttgttttac atctgtcttt atatcctttg ctatatataa 86040 ttcattataa accaattatg gaccattttg tttagggaca tcccctcgag acaatcactt 86100 ttatcagtct gaaagctctt taattaaaga aaaaaaagat tgattggttg ttctggtttc 86160 cagatgaaga atgtctacct ttgtcaacat gcattagttt ggtctttctc aaaacattca 86220 tttattattt tacaaataag gacccagcat aggagcagag atactaaatt tcttccctgt 86280 ttgattaagg gatagatgct gggtggcttt aataattttt agatggtgat tgctaccaaa 86340 gaggtgagga cccggtgtct gggggtagca aaaggcctgt tgaggatgga gcccactaac 86400 atatcccaag agcagcctct gaataaacta aaagtatcca atggctataa atacagtagc 86460 atactctata ctgtgaatga atttctgcct ggaacacatc agtcttcact tcaataccga 86520 agtcatttta aacgaattaa aatgtttagg caattggatt atctgcattt ttacttttct 86580 tatacaaata aagtccttgt agtttgttta gtttgggctt tggcttttca gatacattaa 86640 tttccaaaga gttgattaaa taataaagtg caacttttct cataacttaa atggcagtta 86700 tgagattaat aatctcttat caactaagat ttgacaatat ggtgttcaaa agcaaagtta 86760 gaggaaaatg aaatacatgg aaaatgatcc atcccttcct ctactgtaaa atgaatagat 86820 cagtttttaa aaaggggaaa tatgtagtga ttcctaaagt aaatcctagt accactgtca 86880 actgataatt ttaaatgtaa tttagatttg tagatggtgt aacattaaag ttgtataatg 86940 tttaaaaaaa aaaaaaaagg aaaatactgg ccgggcgcag tggctcacgc ctgtaatcct 87000 agcactttgg gaggccgagg ccggtggatc acgaggtcag gagatcgagt ccatcctggc 87060 taacatggtg aaaccccgtc tctactaaaa ttacagaaaa ttagccgggc gtggtggcag 87120 gcgcctgtag tcccagctac tggggagact gaggcaggag aatggcgtga acccgagagg 87180 tggggcttgc agtgagccga gatggcacca ctgcactcca gtctgggcca cagagcgaga 87240 ctgcgtctca aaaagaaaaa aaaaaaaggg aaaatatgtt atacttaaac tgactatatc 87300 ctgaaaagtt aaaaaaaaat ctgaacctaa ggctagtcaa ccttttgtga cgctctttcc 87360 tccgaaactg tagctgtcaa tcggaagtga tttataaaac tgcctcaaat tcacatatta 87420 caaatgccaa acttttgcat gcatttggca aggactaact tcacacagaa ctgggccaga 87480 aacagagtcc ctaaaagttt agggggtatt ttaaggtcca ggtccaacaa aaaaatttac 87540 ttaattacaa tctttgtgcc ctacctttcc actaagattc acaaatgcat tgtgtcaagt 87600 gataaagaag aaaatgttac gaatcaccta acgtcataca tttaatttaa aatcaatgca 87660 ataatcttaa aaaaaatttt atgctttttg ttttggtttg gtgaaatgac agtcataatg 87720 aacggttgga tgcttaacat aagattcatt tcaagcatgg atatgaaaaa agcacgcatt 87780 caaatattgt ttataggttc ttcaggttat gacatttttg ttaattcttg ccaatattag 87840 tacattaata ccaaaatatt aaataacttg taaaattcta gtttatgtaa aaatgttatt 87900 ttacaggtaa caaaatttct tcaggaaatt aattgatttg ttgtttataa catgacattg 87960 aaattgcaaa cccttgtggc atcaaatttg tttgcatgaa aaattagtac taatattttg 88020 tatagtcttt ataactcatg attttgagat ttccaagtat ttccaagtac agaaagtaca 88080 aaaaaattgt atagtaaatc gaatctgtgg agagaatctg tcaatttgtt aaattagctg 88140 cctctttctt tccttccttc cttccttcct tccttccctc ccaccctctc ttctttcttt 88200 tttttttttt tttttttgac acagtcttgc tctgtctcca ggctggagtg tagtggcgtc 88260 atctcggctc actgcaacct cggcctccag ggttcaacaa gggattcccc tgcctcagcc 88320 tcctgagtga ctgggactac atgcgtgtgc caccacgccc agcaaatttt ttgtatttta 88380 gcagagaagg ggtttcacca tgttggccag gatggtctca atctcttaac ctcgtgatct 88440 gcctgcctcg gcccctcaaa gtgctgggat tacaggcttg agccaccgca cctggcctct 88500 ttttatttgt catggtgcat ttgggacagt tgcatatgtt atgatataat caattcattt 88560 ctcatgtata tgcataaacc acccacaaat gtgtttcatt tcttaaacag aaggatactt 88620 aagattttgt gctaatttgg catgtgttgg tgctacaaca gtccaaggaa tgcagtaggc 88680 aattagcagc aaaatatgcc tgataaaaaa cactcacttt cttattgata tagtaggggt 88740 ccaggtcctc caggggctct gacaccatct ctggaggaat gtctccataa ataaatggaa 88800 ggttctttcc agcttccaag tcactatttg gctttgggcc attttcgtcg tcatcttttt 88860 tgtctggttt gggattcttt gccttttctt ctgcaatgcg tctttcaata gccgcaagag 88920 attctctggt gaagaagttg aagctgtcag gtcctggtgg tacaagcact gtttgctcca 88980 tcttgtcatc ctgcacattt taattaccat ttattctgca tatgaaattc ctaaaataaa 89040 aggaatacag atattttaaa gagtggacta agagatgtta atataaataa attcttgtca 89100 tgaaacatga gctagaggat ttaaagtctg ttttctcctt aaattgaaag gtgatttcta 89160 aagaaaaaat tttaacacaa atggtttctg tgttgagttt agttaagcat cacttattta 89220 ttaattcttg tgctttactg atacaggaac tgtgccatga gttttaaaag tggttcaaat 89280 atggccttaa tcaaagtaca ttaggctaat taacactata tcactaatga gttattcagt 89340 ctgtgacaca cccagaagat ggagactgtg cgtataaagg caaaggatag ctcatttaac 89400 aaggatgagg ggaaaaggaa ttgtctctga gaggacataa aatctaaccc tctaggtctg 89460 acaagtgatt cctggccaag atagtcagga tagtttgcag tgaccaacct taatgaccaa 89520 tcaaatagtt attgctgtct tgactgggct ttaacctctt ctaagatttg agacaactgg 89580 aactatgtcc tgctcacttc actagccatg catggttggc ttacttgaac acataaagat 89640 aaagacagtc cacggttgga caaatgtcat ttatgtgagt aagaaggaga ggaaaactag 89700 gctgtaaaga aattgctaga tggaggtggg ggtggaagaa gatagctgta ggtgcaggag 89760 acagcaggag tctcctgttt caagaaaaat gatcagaaag aagtcagggt gccataaact 89820 caatagaaac taagtgtttt tcttcactga agcaataatg aaattcttgc tgattctata 89880 gtcctatagt gctaaccata ttatgaaggc ctgaggcaaa accgtcaacc ccatacagca 89940 gagtcagacc tgatctgatg ccagacgcca aatcccaaat gtattgtttt aaggcatatt 90000 taatatgagc tcagatttca cagatattac tgagccaaaa tattccagag cctaagctgc 90060 cacttggcca tgaattttat ttggagactg cattaactca ttaaggtcag caagctatgg 90120 tacagttaat tatagctttg gtgtatatga actacaataa gaaaattgca ggcataatta 90180 ttttgtgagg gacagagacc tcaaatttca aggaggttct cattgttgtg aggtttataa 90240 ccatattttt cagagtggat gatcaaaaga agggaggact caagtttaaa tttgtaccct 90300 tagtctacta agtgaagttt tcagcggttc ttagaactta acctgcagtt atttagtacc 90360 tgcaagaata ggttgtctgt aaatcaatga aaactgaatg ttctgtctac aaactctggt 90420 tcccctacaa ggcatcagga aaatactaac atttattttt tgcaaataaa agtttaggga 90480 taacaaatat agtaactttt ctcaaaaggg aaataaaata ttctgatgta tatatatagt 90540 ttttattttt aaatagcttt ttgatagaaa atatatgtaa atgatataaa tgcaaatatc 90600 taaaagaaaa tgcagtataa tatctccttt ttaccttgtt tccccaggcc cagttcccct 90660 tcctagaggc aactactact acttatctcc catatatatt tccaggtatt caataggtat 90720 atgctagaac atgagtgtat gtatacatat tctattttaa aatacatatt caaatggaat 90780 cttattatac aaactgtttt acaccagcat tttttactta aaatgtatat tagagttcat 90840 ttatcttaat ttttatagat ttgactcgta cctattactg gctacatggg tttccattgc 90900 atgttatgtg ccataattta tttaaccaat tccctgaatg tgagtatttg ggttgtttcc 90960 aatctttagc taatattgaa taaagttgca agtaatacat ttttacacac atactttcaa 91020 atatatgtgg atatatttat aaaattaatt tttaaaggta gacttggctt tgtacagaat 91080 gtttatttat gatagttact gcaaaactac tttctatgga gtttgtatga acttattctc 91140 ctgacagcaa tgtaacagag tgcctattta tcctcaccaa tataatatgt tatcatattt 91200 ttgatatttc caatctgaca gggacaaaga tgagagcata ttataatttt aatttgcatt 91260 tgtcttacta tgagaaaagt ggaatatatt tttcttatac ttaagaatta ttttttattt 91320 tctttcctgc aactgcttat ttaaaaacag cccatttttt ccttctattt ttttcaatct 91380 atagcatctt ttaagacaaa atattagcca cttgattttt tgatgtgtgg tcttttaaaa 91440 atgtatattt tttgacttta tggtgctttg tgctacagat tttaaaagat ttaattaaaa 91500 atgttaaaat tgttaggtga ttatctaatt cttctttggc ttctggatac tgtataatgc 91560 ttagaaaggc atccagagag atgggcagta aggggtagga aaaaggatat aaaatatata 91620 catacacaca catgcatctg tatcaccttt ccctcttgta tttttagtat tttggtggtt 91680 taatgttata agtttaaata ttttatctat ttggaattta ttttctatat ggagtgaggt 91740 agagatcaaa gaacaactaa ataaatgcag agacagtcca tgtctttgaa taggagtgtt 91800 caatatatca aagacactag ttcttcccaa cttgaactaa aggtttaatt taatttctgt 91860 caaaatccca gcagttattt gtggatattg ataaactgat tttgaagttt atttggaaag 91920 gcaaaaaacc caaaagagcc aacacaatgt tgaagaagaa caaagttgga ggactgacac 91980 taacccaact ttaagactta ctgtaaagct gcagtaatca atacagtgtg gtactgacaa 92040 aagaatagat aagtggatca atggaatagg atagtgagtg tggaagaagg cccacataat 92100 tacagccaac tgatctgtaa taaagaagca aggtaataaa atgaagaaaa gatagtcttt 92160 tcaacatgta ttgctggaat aactagacat ccaaatgcaa aaaaaaaaaa tgaacctaga 92220 ccttatgcct ttcacaaaaa ataattcaaa atggatcaca aatctaaatg taaaatgcag 92280 aactaaaaaa ctactagaag ataatattgg agaaaaccta gttgactaaa tttgttgata 92340 actttttagt tctctgtttt tcttggaact gtctcatctt catatttgag ttctggaata 92400 tttctggtga tattctcagt gctatatatt tgtttttggt tttctaggag tgatggtgag 92460 gaggaattgt gccagcttgc ttcttcactg ccattttgga accagaactc aggtgatgac 92520 tttttagata taacaccaaa ggcacgatcc atgaaaaaaa agaattgaca atctgatatc 92580 attaaaatga aaaattttgc tctgtgaaag atactatcaa gagaatagga aggcaagcca 92640 catactaaga aaaatatttg caaaagacat gtctgataaa ggactgttac cccaaacatg 92700 caaaaaatta ttaaagctca acaataagaa aatgaacaat ctgaataaaa aatgggccaa 92760 agacctgaac agacacttca ccaaagaaga cacacagatg gcaaataagc atatgagaag 92820 aagatgcccc acatccatca tatgtcatta gtgaaatgca aattaaaaca ataagatagc 92880 actacaccct cattagaatg gtcgaagtcc agaacactaa caacattaaa tgctgatgag 92940 gatatggagc aatagaagct cacattcatt gctggtgggc aagcaaaatg gtacagcaac 93000 ttggaagaca gtttagcagt ttcttaaaaa ccaaacatac tcttaccata tgatccagca 93060 attgcatacc ttaggattta accaaaggag ttgaaaactt atgtccacac aaaatcctgc 93120 acacggatgt atacagcagc cttattcata attgcccaaa cctggaagca accaagatgt 93180 ccttcagtag gtgaatggat aaataacctg tggtacatcc agacaatgga atattactca 93240 gcattaaagg aaatgagcta tcaagccatg aaaagacatg gagaaacttt aaatacatat 93300 tactaattga aagaagcaat ctaaaatgga catacagtat gattccaact atatgacatt 93360 atggaaaaga caaaactaca gagacaataa aaagatcagt gattgccagg gcagtgaaaa 93420 tactttgcat gacactgtaa tagtggacac atgtcattat acatttgtgc aaacccatag 93480 aatgtacaat accaagattg aattataatg taaactatgg actttgggtg attatgatat 93540 atcaaattgg gttcatcagt tgtaactata tacaatacct aaacactgtc tctaaaatag 93600 ctcttgaatc aaagaggact ttgattctaa tacatataat atagcacata tgttaaaata 93660 tacctatata caatacaggt atatttgaac tgcgtttaat ttgttaattt agggaaaaaa 93720 ttaatttttt tcctaaatta attttcttcc attgtatttt ttctcttcta aatagattat 93780 ttttacagta atacatatgt gctactctgg tgcgagatat tgatagttgg gggaggctct 93840 gcgtgtgtag agaaagggga aactctatat ttttggctta attttgctgt gaatctaaaa 93900 ctactgtaaa actagtctat ttcaaagaga aaaagtacaa tggaagaaat gtttctaaat 93960 acaatgtaag cattttttaa aagctttgaa taaaccaaaa gtaaatataa atggatggaa 94020 agttatatcc tattattaga taggaatgct atatcataaa gatattaatt ttccctaaat 94080 taataaatta aatgcagcct ttgaaaaata atcacaaaat tcatataact agagaaatct 94140 atttgagact tcatgtggaa aaataagcaa acaagaataa ccagaaaatt cttaaaatga 94200 attttggttt caaagtcctc actgatgcaa gaactattta aaagaaagtg tttaaatttt 94260 tcaaatgata gattttcctt ctaagtttta aatttatgtt tagttttatt accctatgct 94320 ctgataatgt agttcgtacc atttctgttt cttggaattt attgtgattt atttttatcc 94380 taatagaggt tgtttttaaa atgacttttc taagaacatt aaaaagaaac ttattcttta 94440 ttttaaagca gtagagttca ttatgcctca attatattga tcttatttct tatcttatgt 94500 agaccttcta tgtctgtaca tatttttttt ctacttgact gttccaagtt gggagaggca 94560 aattaatgtc tatttaatgt gtttttattt attgtggttt ctgtcatttt tgttctatga 94620 attccaatgc ggtattgttt gatgtgtaga taacacttat gatcagatct ttggagtgaa 94680 ttgaaccctg tacttcctta aatggccctt gtttatctta ctgtagtttc ttccctttaa 94740 agacaacttt gtctcatagc atataatgac tttaatttct acttatttgc acttatctag 94800 tatgtctttt tccatcaatt cggtttcatc cttttcattt tactgtttta gcactttcct 94860 taatatgtat atgtttagat atcatatata ggtatatttt aacatatgtg atcattacga 94920 caatcaccgt ctttcagagt gccacacttg atgttattgt ccatgaagtt gtgtgaatgg 94980 acagaaacag ttactaaaag ccttcctatt ctccagaaat actgcatttg agaaaagctc 95040 tctaaagaaa atctccctgg tcactagcta tcatttactg gagaaataaa caaccaagaa 95100 agtagaagac atgaattcta cactgacaaa tatgatcagt tcaaacgtat tatatataat 95160 tataaattag ttagatacag gaattatatt catatgtaag caatataacc catattataa 95220 tgaaatcata ctgatactag aaaaagtatt tttttaactc taagtagatc ttctattcaa 95280 atgctaccta aaaataaatt atgttatatt aattataaga ataaaactca ttaaaaatct 95340 cataaggtta attatgaaat acctaaaaaa ctgtcagatg tcattcaata ttaatatttt 95400 ttagtaatat gaaaaattgt tctaaattac atttgaaatc tgtacttatt ctattaaaat 95460 acagaaataa atcatgaatt ttccatttac acttacaaag gagatttcac ctctttattc 95520 taaaaattta taacagaaga cttaattgtc ctaatttatg aaaatacatg tcactagata 95580 cggggtagta acctcataga atctgcagtt ttggcttaca gctttctctt ttcataaaaa 95640 ccagcattta aatatttggt tacatagagg agaccttgct cctttcaaaa gaggtaagac 95700 aatgaaactt tcctaacaag agaagacttc aaagagagag gccttttcaa gatgattatg 95760 gttatgcatt tggacaaaat aaaattaaga agagaactaa gaaaccatag ctaggaagaa 95820 aaagtaacaa agtgcatgtt agcaaacttc aaatctgaag gaattttaaa aaatattgga 95880 aataagtaga gtagtgggca atagaaaact ggaagaagaa tgattctttg gaagacaaga 95940 aaaatacatt aaaagtggaa ttcaattaga taagcaatcc taaagaagac aggaaaaaaa 96000 taatccaaaa gaacatgaaa tggaagtgag agatcatggg ggaaaaaaaa gattgtaaga 96060 aaatgaagtg gaaattttga gtggaaagaa atagtaaagt aatagcaata acatgaccaa 96120 tatcaaataa cgtggacaaa agaattataa ggaaaaattt gttagaatat acaaataata 96180 aataaagata taatatcatc tggtaatatc taactgaaag aaaaagaggg aggtaaatct 96240 gtagcattat aattaacaga ttaccttctc gggagacttt acaagatcag aaagttaata 96300 ctgataatat tcagtgtcat ttctaagact ttactaattc attacttatc ataaatgttc 96360 tagtactaga tgaggttttt gcttctgggc attatatatc tctgtttccc gtagaagagg 96420 acacatgtat tacgttctgg acttgaggag gcatttatca cagccaaaag atgtttatac 96480 ttgaggtgac tgggagtggt aaaccatatg gctttggtga ccctcaaagt gcagatggag 96540 gagctttatt taaagtaatc ctaacccatg aagccttaca gttaaactcc cttgggcatc 96600 tgcttttctc cagtcaaaca aatatgtacg atagctcaca atgaagtatt tcattttccc 96660 tgtggcattt cacacagaag tcttaactgt aaaggcaacc ttataaatgc tttgtacccg 96720 aagaaactgg ccttttataa gtaaatcatt atgtagtttc ttcctttgga gggcagctct 96780 gtgtgactgc ttgggcctct gtggttagat ctgtttggtt aacgggcttt tgggctttca 96840 cacaaagcta tactctccac aaacttctgt gagataaaaa ggtgatatct gtcttagtcc 96900 tctgaatatt ttttctttgt tcagaacctg agaaagatga atgaaattta gtgtttccca 96960 tccccgagag acacccagca tccacaactt cacactctga tgccattgtg tatttatgca 97020 agaaatacca taactaaggt aatgtcttga gattttttgg ttcaataatg tccttaaatt 97080 ctatgttgtt tttaaagcct aaaagaaatt ccccctcctc actcccccgt ctctccctac 97140 aacctggtga gacaattctc tcattttctc ctcccagttt ccaatgctat tgttatgatc 97200 tattagaata attgctatta tttttttgcc ttatctgacc ctagaagtga tttacaggga 97260 aaaaaattac taaccaattg attagtgaac tgaatataaa gtgcagctct tatggtttat 97320 tcacagacaa gaatatatat agtacttaat gtgatagtat tttgttgttg atgtggaaca 97380 gtgttagtct ataatacagg ctttcaggca gacaagacct agtttacctt gacctctgga 97440 cttctgaaag gttgagtaag ttattttaag agaattagac aaagataagt aaatcaaaac 97500 caataaatgg caaagattta aaaaacagag attagtctat tcctctcatt taatagaaaa 97560 caaactgaat caaagaaaaa tgggcaattt ctttgtttag aacttatgtg cttcctactt 97620 tcaaaataaa tatgtcattt gtcccaggtt acgcagctta ttaatggtgg gacttaaatc 97680 agaactttta ttttctaact cccaaaccag tgtctgccag gtcctaatag ttatgaaata 97740 ttcttttaaa gctaaataaa atatatgaaa atataagtag ctgtgttaaa atagtattta 97800 tctactctaa ttgatctagg tctctccaag gaatttatat tacttggaca gacccaaaac 97860 aaatacagta aataaagcat tctggcaaaa atggagactt caaaattttg aaaaatggga 97920 gactccaaaa tttaaaaaga tgattgtaat attcaagttt agaatcatat gatgcaggtt 97980 ttaatcctgc tgaactatac ctccaccgtc aatttatgtt ttacttccgt tatgttttat 98040 gtattgctaa actggattat ttctagttac taactgagca gatgacttta tataatttat 98100 ctgtaactcc aaagttcaat atagttgtgc aacatttata tatcttcacc accttataat 98160 atataatctg atgtggagaa aaattatata tcttcaattc tgtctataaa gtagtttaat 98220 atccatactg aagagaaacc aaaaagactt ctgccaaaat gcttgccatc tccttgtaaa 98280 gagctattac tattctgggg acataaacca tctgggcacg acaatttgtg aagtgtttca 98340 gttcgttttg tagtgttctt gccacctact ttacaaaaga atgttactgc caataataat 98400 aaaaataact aggtaaaatg ttattcttac tgttgtgatc tcacataact attttttagc 98460 agccaagaaa gaaattggtt tttacataga aatcccaaac ctagaaagta ttgttttata 98520 aatttctttt ctagaaataa tttgatttgg tgtaattata attacaaaaa tatttcattt 98580 gatttctcaa taagccaatt tttagtaggt tggggttaac taaaacaaca tatttcagcc 98640 atatgtttaa aacttttaca tttaaaaata acttcattat ctacccttag tttttcatgc 98700 cttatgcaaa ctgcagttaa aataaggtca gatatctaac atatgtctgt atctacattt 98760 gtatactcca ggggtgtttt tcaagacacc ctaataataa actaagaagt aaaaaattca 98820 ttcaatctac atacaataca tagaaataca atacatagtt tttgcctgag attcagatct 98880 caggcaaaaa attcattcaa tctacataca atacatagaa atacagtaca tagtttttgc 98940 ctgagattca gatctgccat agtttattag gctctgcctg tagttttctc atgaaacaca 99000 tcagtatcat taggatgatt aatttcattt ttttccttac agagaagatt gtcattaaag 99060 agtaagacca tggatagttc acataataaa tcatgtgaaa tttaggatct cttctagacg 99120 atcatagtca gaataattta agggaattcc tttgaacaaa tgtcattagt ttatatcaag 99180 aatatagtaa tgactgtcat tgtaagtaaa ttatttaagt taacctcttt tagtaaagtt 99240 ttcctgttag aaaataagta atcttattgt gtgggtgagt ggtcactcga cagagatttg 99300 ggaggatgta gagagtgaag tctaatcctc gtgactgtga ttgtggttgc agattttgag 99360 ataccaagtg tgaggtgata ggcacttaaa gcccagtgtg ggcctcccag ggctgtttag 99420 ctagcaatga gagaggcact gcctatatcc aagttgtata tggcaggttt tgcacaaagt 99480 ggattactcg aagagaaagc ctaatggcca gtctattcat cttccccttt ctcgatgttc 99540 atcttttctc tcccagctct cctttattct caattttctt tttttttttt tttttgctca 99600 gcctccatct cacttccgtt gctgtcctct ccccacccct tcccactctg gactgtgcct 99660 ctcctttgta gacacttcaa gtccattcta tttcattcaa aaaccatggt ctagaagtaa 99720 cttaatgtaa acccacaaag atggagacag aatgaatgcc attcttcttg ctgctctctc 99780 agacaatgca ggtcattttt gcctatggtg ctggtaaagc caggagttat gtagctataa 99840 gtagcagcca gaggaaatag tgcctgagtc agcaattgtc tttttattgc tgtggggcaa 99900 taatgggaga aaaaatcagg cttggtacaa ttccctttga aggaaaaaga tgccaacact 99960 agcattttaa cacaaaatgc tggttggggg ttgggaggaa ggatgcttac attccttctt 100020 tggaaatatc tactttgata accattttgg taaaataatg cagtgttttc agtgtgcaaa 100080 tcctttcagg actcatggtt gtatggcaga cgcacctgac agcaataatt taagggtacc 100140 ctgagaatga ctctgtggtc taaaaagaat gtgtgtttgg aagtctgagg taagaaatct 100200 ggctggaagt ggccaacctg gaaatttgct ccttattatt aaggatttcc aaagcctggt 100260 ccattcctca gaatgtgggc catacagtgg atgaagccct ttgtttggat taaatgaatg 100320 ttgctaggtg gagagtgcta agtgaaaatg ctatataaac tgcatgcttt ttacaaacat 100380 tagtggttct cccatccagc ccactgccac tggaccaccc ctgtatatga gtcctagata 100440 aatcctatgt ctcccttgct ggcttcaagt ctcttcttta gtctcttggc catgatgcca 100500 tccctattgg actcaatggt gttccagcac aacaatggta tgattagact ctgttcctgg 100560 gagacataca ataccctcct ttggtaggat ctatgtggaa tgtttagtca ttagtgttat 100620 taagaaatca tagttattta atttatgttt taagactttc acctttcatt ctctgaatgt 100680 tagttagctc agggtgtgaa atggttcaac agaaatactt gagctgctgc agccagaagg 100740 atgtttatgg tgttatgcag gaaatatcct gcagaattct gtgtggaatt ctgctcagag 100800 gggtttctct ttagcataaa ctcaatttaa aaatactctt ctgctcaaaa gcattcttat 100860 gaaaccacct caacacaaag caaaactgtc caggcatagt tgctgtatgg agagatacag 100920 catagaaccc acgggcagcg gggctgaagc agagaaaaac tgcaggggaa agagaaacag 100980 atccaggaac ggggagagga gagtgttgag cacaaattaa ctaccctggg gaatgagtat 101040 caggtgtttg acactttcac ttttccaaat aacctgaaga caaatggaac ctccctgagt 101100 tatgaaaaat tgagactaga agtatcagag ctgcagaatt catttggttc agattctgta 101160 tatataaaat ctagacatag aacaagtcta agcaaaggca tattatctgc aatggttact 101220 atggattatt gttcagagaa gaaccatttt ggtatagaga aagctgaaag aacttacaga 101280 aaataggtct tgaaagatga aaggcagaga taatttcctg attcagaaac tcagtatatt 101340 aaattttctg tatgttattt atcatttatg atataaaatt atgcttaatt tatcatgtaa 101400 actgaaaata aaattctaag ccccctgact gaattgacct tctcctggcc aaaaggatcc 101460 cagagtaacc ttgaagactg aattctcagc catggtggat cagggagtca gacatacctc 101520 cttataaccc ctccctcact aaccactatg aggctttctt ccctaagggc taaacagaaa 101580 tcagcccttt caaaagactc ccccactgac atggaccaac cacctgacac tttccctcca 101640 ttggtgcctc ataagagacc acccactagg gaatgattct agccattcca ctgagaatgt 101700 gcagtaagga tttttgtgtc ctctgcttca ccttttaatg tcagagggcc gaaaactcta 101760 ccctcggatc atgctaatgt cgccattttt tccacatgga tcccacaaag gggcatgaag 101820 ctcagttgag gatgtgcatg cttctcctct cataaatatt catgactcct cctataactt 101880 attgaacata tatatttggc caccgtgctt agcataaatt tctgtttcct ttttccctcc 101940 cttgaagtgt ctgtttctgg cttctggctg gaagttatgc ttcccaacct gtcagaaggt 102000 cactctgcag gctgcagccc tttataagaa ataaagctct cctttccaaa tttatgaacc 102060 tcatcattct tcaggtgata atcatataaa cgtctactta agtttgcttt cagtctgtca 102120 tgtgaattca gtcattctca ctatattcct tttgtggtat actggtctgg gttaaagaga 102180 ccctctaggg attattatac agtttcgtct tgtttgagag ctcagcagct gatgattatc 102240 acagatttgt atagagtgga cactaccaga tgtccagcac atctgtcaca gcagatgtga 102300 cattgagcca agtctatttc tgtctaggtg tatgatactt ggtgctatac tttggatatg 102360 gtttgtcgcc atcaaatctc atgttgaaat ttgattccta atgttggagg tggggcctaa 102420 tgggaagtgt ttgggtcatg ggtggatccc tcatgaatgg tttttgcctc attctcactg 102480 taacgagtga gtccttgctc tgttagttct catgagaact ggttgaaaaa aaaaaaaaaa 102540 gagcagcctg gcacggtggc tcacacctgt aatcccagga ctttgggagg ctgaggtggg 102600 tggatcacct gaggttggga gtttgagacc aggctaacca acgtggagaa accctgtctc 102660 tactaaaaac acaaaattag ctgggcatgg tggtgcatgc ctataatccc agctacttgg 102720 gaggatgagg caggagaatc gcttgaacct gggaagctgg gagggagagg ttgcggtgag 102780 ccaagagcat gccattgcac tctagcctgg gcaacaagag caaaactcca tctcagaaaa 102840 aaagcctggc accccaccct gtctcttgtt tcctctctgg ccatgtggtc tctaccccac 102900 acaggctgcc cttgccttct gtcatgaggg gaagtcacct gaggccctca atagaagctg 102960 attctggtgc catgcttctt gtacagtctg aagaaccata agtcaagtaa acctcttttt 103020 aaaaaaaaaa attacccagc ctcagatatt cttttatagc aatactaaat ggactaagaa 103080 acatggtcta tacagtcaat tttgttcatt tctttaatat ttattgaata tagacaatgt 103140 gcaaggcact ggttagagat gtggagacta tgaagttggc aaatagagaa taataatatt 103200 gagaatcctg caaagtaacc aaattgattt tagaagctcc tttatgaaat agactttagg 103260 ctttagtctt cttggatctt tacttggaaa tttaggtatt cctgatttta acagattcat 103320 ttttttaagt cccagagtag aagaaaatgg aggttgaaca ctgaaacatt gactttgaaa 103380 actgaacatc tctgtcaatc ccacaatctg tgtgtttgtg tgtgtgtgtg tgtgtgtgtg 103440 tgtgtaaggg tatgagctac aacacaatct tgaattgtca ctaaaccatt tttaaaataa 103500 ttggtcaacc acccatcaca tcacttgtat tcacaatccc ataaagttat cagaccagag 103560 tgatttttct ctaatctaga tgtacattaa aatgtgcatc tcatttaaag atagttttgg 103620 tacatcaaag tgaatgttga taaacatgta agacaatgga atataaagtt caatgcatgt 103680 cctgcattct ctccatctaa ccatttttgt ggtgccaatg cctattttca ggtgtcaatg 103740 atgaagaact ggaaaaagat atagttaaaa caaaaattgc taaagaaaaa aatgcatgct 103800 tttttggatt catttctact ctttcatatc aatatgtttt ctaacatttc ttaagtgctg 103860 agaaaatttt cctttttgtt atcctcaata gcaggtggca gctgaaattg ttcaattata 103920 tgctttgtta aaaccttata aataatttaa atactattat tacagtcagc taaagcctat 103980 gctcaaatta tattttcttt tgtttaaatt cccaaatata tctcacctgc taccctacat 104040 tcacccccag taaagtccca aagcccgtgg gctaggtagg gcattattgt tttagaatgt 104100 taccaagttg gcctagaaga gtacttgatt tgttgcgaca actgttgttg ttctctaggt 104160 agagtgttgc gtaaaggaaa cagtgatgtc caaaggggct ggactggcag attggaagta 104220 gggagaccca aggtcagcat tatgacatgg aggatatgag taaccaccat aatgatttaa 104280 gatatctgaa cagggttgcc agaaaaaata catgccacac agttaaattt gaatttcaga 104340 taactgattt cttaaagcat aagcatacct catacaattt gttttatatt tactatactt 104400 taagttctgg gatacacgtg cagaacttgc aggtttgtta cataggtata cacgtgcctt 104460 ggtggtttgc tgcacccatc aacctgtcat ctacattgag tatttctcct atccctcccc 104520 taggccccca cccctcgata ggccccagtg tgtgatattc ccttccctgt gtccatgtgt 104580 tctcattgtc tatatttggg gcccactgct agtaaacatt attcattgtt tatctgaaag 104640 tcaaatataa ctggacagtt tgtatgttta gtttccaaat gtagcagccc tatatatgaa 104700 gaaagtcttc tctgctaaaa aaattatttt cctgcttcct gaaattcaat taattagcat 104760 tttcagttca gttagcaagc gcttcctttt aaaagacaag tatctctggg agtacatgag 104820 tcgtttatgc atcaatgaga ctacttactt ctcaatgtaa aatgcatttc tcactgtcaa 104880 agtgggttaa tcaatcagag agagggcgta agagttcttt ttttggttga ctaggtaggg 104940 gatggggctg gctgggacct gttaatttca gtggaagaat acatatggat gaattacttt 105000 tagtggggat tttctgatgg aatgaattat caatgtgcca ggaagagact atataaaaag 105060 atggaatggg ggtagagagt gtaaggtggt actgacagaa aaaactcact cattctagga 105120 tttttcttga acaattaaat actcatgaga ggaaccagtg ttgggtttta tttttcaaac 105180 atggatgatg gtaaatgtta aaaccagtgg caagcatatt ttcacatttc tttcattatt 105240 aaaagtattg atgtaagatt atcctcaaat atatgagtag tgcatctttg cacattaagg 105300 actcctcctt tattttatca cttcgcttta actccgtagg tcctatacaa accaaagaaa 105360 ttatcttcct tccttccttc cttctttcct tttttttttt tttttttttt tttttttgat 105420 atagggtatt gccctgtcac acaggctgga gtgcagtgat gagatcatgg ctcactgtag 105480 cctcaaactt ctggccccga gtgatactca cacctcaggc tcctgagtag ctgggatgca 105540 taccagcatg cccagctgat ttttaaactt tcgtacaggc agtatctctc tatgttgccc 105600 aggtggtctt gaactcctgg cctcaagtga tcctcttgcc tcagcctccc aaattgctgg 105660 gatgacaggc atgagccatt gtatccagca agaaagagaa aagaatttaa acttctaaag 105720 atgaaactgc tacacgtgga cagccataac aacaaagaga agagtactct taagcatttg 105780 tgaaagtcag aaacctataa acttttggga aacaaaataa gtatattttc cctttaatct 105840 tacaagtgat gcaatacact tctagcaaaa gtgaaagggc aaataggaat tttgcaacat 105900 tgagctctct ttaagcagaa gccaggccat aggttcttca ctagtcacca gggtctacag 105960 cctttattgt ctttaccagt cactaggtat gagacatttt ctcataaaat gtaactacta 106020 tacattcgcc acaaacttta aacccccttt tcacctccca tggtacccag aagagtgata 106080 ggtacttaat aggtcctcaa aaattttcag ctaatgaata attgttaatt aaaacttata 106140 ctagaagcaa actcttaaaa catattctaa gtactaaagt ctaatatttt atatctattg 106200 gtttattcat attcttgttt gttaatccta atcaaatagt gcaaagttta aatttcattt 106260 tcctaagatt tgttttaaaa taacacgatt tacccaagtg atttcaaacc acaattacat 106320 tctgtttaaa ttactaatat tttattgcat cacaatctgc atgaaacaga tgtcaggata 106380 taatgaacta acctgcattg tatttttatt tttgtctcct gtggcataac gatttcatag 106440 gaaagagaac tacacagctg actgactgat ggggaaagtt acacaatgga tagctttgca 106500 gcaacatact aatgcggtag ggagatgctg cagagaggct agaaataaaa tcatttcttt 106560 ccggagcagc actgcttgct gtcggctgag acaaaaaaga gatttccttt ttttcctttc 106620 ttttttttga aaactcacat aacattaatt ctgttaagca ctggatacac ggaaaggtgt 106680 ttaccttaga aaatcattta gcaattttta gaaactagac atatagcaat tttaaatctt 106740 tttaactatc taatgaccaa agcagagggt cctcacaaga gggatttaga tgctactgaa 106800 ttgaataaag aaaatatgga tacatttatt gtatgcctta ttcagtttga ggttcatttt 106860 gagtttagaa atagggatat aaaaacatca ggggttaaat agcatgggta aaggacatga 106920 accaagctgc agagaagagg ctgactgcct gctatatttg caggcattac tcagcacttt 106980 tcttaaaccg atacatcttg ctggctgcat aagcaagaca agaccctttt ccctatggct 107040 caggaaggca gagaagtcaa cttcagcctt gaaaaaggca aatactttag tgcaataatg 107100 aaatcaacta aacgtcttgt gcttaatgtt tctttcccca cgccactaga attgtatgca 107160 taatcattct atgcaacata ttgaagaaac caaaatgttt gccacagtgt gctcagtaat 107220 ttttttttga atgaatgaat aactgaattc atgatcaatg ccttatccta ggtcacctgc 107280 tcagtgcacg ggctatagga agggcaaatg tcactgtcct tcccacccat ctcattctaa 107340 cacaagtgtt atcatcaaac taaggaaact aaaacatgta gccataaaac aactgtttag 107400 agcttcattc agataatatt tttttcttta aaatccaaga atgtaatacc aaattttaat 107460 taagcgaagg cgtctttgtg gagaacttaa ataatatggc atattgcttt ctgtttatct 107520 agtagagact acactttgaa aatatagacc attgcattca taaaaatcat gtggagatct 107580 ttttgaaaac acatagtcca aggtcccacc tcaagatttt gtttcagaga tctaaggtgg 107640 acctagaatc tgtgtttaaa ctgcttgtcc aggtgatcag gatgtagcac tcatagttaa 107700 tgaatgggca aattttgaga aacactgttt tagagaatgg tctaggaaaa gcatccatta 107760 caaatataaa aaagcaagct tttggtacct aagggactga gtcgattcat gcaggtattg 107820 gtttgttgat taaagatgca tccataattc aattaattta aatgttagaa caggtcatat 107880 cttttgggtt tatttttaat tgtttcgtac agatgaggtc tcgctatgtt gcctaggcta 107940 gtcttgaact cctggcctca agtgatcctt ctgcctcagc atcgggagtc actgggatta 108000 aaggcatgag ccaccatgct caggtaggaa aaaatcattt cttacatgga gatttatttt 108060 ctcaaccagg taagttttgt gataagatca ttaaacttag aataagaata gtcaggttca 108120 aaatttggtt gtagtcctta acaaaactgt gatattaaaa tagtaccttg gccttgctta 108180 gcttcaattc tatcatttat aaaatgggaa taatttttat aataacacat gataggtgcc 108240 aactcagccc tcactccttt tttgaaattg tcctccatgt aacccatact gaaagtataa 108300 actatgttta taccatgtga ctctttcacc cctttcccat ggccacagct tggtaggttt 108360 tatgaggacg ctgatcacgg ggcactcatc tataggctta actgaaacaa tagaatttgc 108420 tttctgggtg atgtttaaat gaagtaagag tgagtgagtc agaatgttat gagaagatgc 108480 actgcatgac ctagagttga ggatgaggaa gctatgtctg gccatgacca agcagaggat 108540 atcggccaaa gcagaaaaaa aaaacagaaa taacagtagc catgcaagca ttcagaaaga 108600 atgtaggctg tgttgatatg tttctggact tctcattcca gtttaatctc tttatggctt 108660 acttgggttt tggcctatgg gattttcagt tgaattcttc tttttttttt tcctttgaga 108720 tggagtctca ctctgtcgcc caggctggag tgcagtggcg tgatctgggc tcactgcaag 108780 ctccacctcc caggttcacg ccattctcct gcctcaacct cctgagtagc tgggactaca 108840 gttgcctgcc accacgccca gctaattttt ttatttttat ttttagcaga gatggggttt 108900 caccgtgtta gctaggatgg tctcaacctc ctgacctcac gatccacccg cctcggcctc 108960 ccaaagtgct gggattacag gcgtgagcca ccatgcatgg cctgaattct tataataaat 109020 aaaccatttt acttataccc gcttaaatgt gcctttatgt tttgaataca agtgttctga 109080 caaaagcaca atgtaaaaac actgaacata acatgttctt aacttttgtt ttaaaacaaa 109140 agaaaaaaat ggaggttcag caaagttaaa tagcacaagt taataaagtg atgaccattg 109200 tcagacagtt tggaggaagt ttgagattta aatccgggtc taatctttca cagttcaatg 109260 ctcttgtttt aaaaccagaa attcaggcag caagactgat atttcattag aaacacttat 109320 gaccccaata tgttttcaca ttgagaaact gagtcattcc actttttcat gaaaatagct 109380 aaaagaatcc ttatcggtca aatctttcac acacacacac acacaaaaat gatctttaac 109440 attatttcaa gtacttggac aaataccaag ttgggatacc agagatctat gttatgaagg 109500 atggataaaa catctgataa gaaaaaaaga aagccattat tattacacct taaatattaa 109560 atgagaaaac aaggaatgac ccttggagaa cgactaattt tgagaattgt atactgatag 109620 acgtgttgga atggactact tgcaaacaga atcactgagc cacttaatga gttgagtggt 109680 tgaaagtgtc cttttaaatg atcaatttag accccagaga atatctgcca gacagaacaa 109740 gttttagtgt agttgatagt aagttgtgcc cagaatatta aattgagtca aatttatttt 109800 ccacataaag tcacagtttt atatgtcatt atataatctc ttggcagaaa taaggaataa 109860 cattctgaat gttgcactcc aaaattcaaa gaatcttagt ataaaaatat ctagcatttt 109920 agatgtttca aagtagggcc aaatgcagaa aataagttgg atatgataaa aataccagaa 109980 agttctattc agttggcatc ttactagcag tttcatcttc taataattta gttgctacgc 110040 atggagtaga atagaattta acaacaacaa aagatcatta aataccaatc aaccaaacaa 110100 ccaaacacca aaggacctat taaacttcaa cgatgctcag ttatactctt gagggtacag 110160 ggctatcaga gatgggcagt gtgctccttt cctgtgtagt ctatgggatc tatctatgta 110220 accctccatg tgctcctacc cttccccttc agctgttaaa aacacaatgc caaaatcagg 110280 atcaaacaaa aattgcagtt acacttctga atttggcaac atctatttca ccactccttt 110340 tagatcattt ggtctttatt attctgcttt atattgtatt tgattttgta agtcagatca 110400 aataattttt ggaaatagaa aacaaacaaa taagctcccc attgctacag tttataccca 110460 ttttaaatga tttatctttc catagggata aaaattcaat tacgtaccct ccttgtgaca 110520 aacctccata caattgaagg cagttattat gtctctcttt agttttctct tttccaagct 110580 gaaaaatttt caatatttta acccataggt atgatataat tatttgtatt cctcttttgc 110640 tcccttctaa tttctgccca acttcactaa tctccttagg gtagaaactg taatagaata 110700 atggtgataa gaacagtaaa aagatgatgt ctgatttttg tatacatttc ccttagtacg 110760 aattactgtg tcaagttttt tagtaatata atacctttat ttagcctttg tcattgtaca 110820 agccagtttg acattttaac aaagggggat tgaaacaata aaactgatct ttaaatataa 110880 aaatatccca tgatcccatg attctcctgt tcttcctgct atcaatcaga aacaacgatg 110940 cctgttaaat aaaagagcct tattggttct accaaatttg tgactaatta gcttctctgc 111000 catcctgtta tttgtatagt ttgttcttgg ttcaaaatat actacacgct aaccaaactt 111060 gacactagag tctcacttgc cttgatgggc caattcctaa aggtttcaag gttattctgt 111120 ttcctattta tacattcctc agagctatta atatcagttt cacttaaaat ttatatttaa 111180 tgtcaatacc cagcatgaaa aactattaaa tggtaatagt ctttagatta atttagataa 111240 atggtaatta atatattttt ccaggatgtc ataaaatcat cattacttac cttgaaccac 111300 ttgaaccctc ccctaaaagc aatatgatac agatgaataa ttgcagaaaa ttaggcccag 111360 atttattcta aagttttcaa gaattcataa tgtcccactc cagttttgga ttcatgttaa 111420 atacatgtct tacaaacatt cacactatat tctttttaaa ttatacaaat gtaagtattt 111480 aataaaatgc aaattctctc aaagagttat tgactccaca gaagactttt gagagtcaat 111540 gtctattgtt actatcaact gacactgaaa gttcaatttc tttcattcat atggtagtcc 111600 ataattctga tatgaaagtt ggaaatcagg gatgaaaaat cacttttttt tttggttgtt 111660 gttacagagt ctcgctctgt cgcccaggct ggagtgcagt ggtgtgaatt cggctcactg 111720 caagctccgc ctccctggtt caaacaattc tctgcttcag cttcccgagt agctgggatt 111780 acaggcaccc accaccacac ccagctaatt tttgtatttt tagtagagac agggtttcac 111840 catgttggcc aggctggtct tgaactcctg acctcgtgat ccacccacct cggcctccca 111900 aagtgctggg attacaggcg tgagccactg cgcccagcct gagagatcat gttttttata 111960 agaacatata catgtataga tatgcaaata ccttcttaaa gcacagataa gtggtatcca 112020 ttattttttt cttgatcaac atgacatttt gcttcaactc aaaagaaaat tacattgatc 112080 tgacaatttc ttttcacaag gtcatagtaa ttttattcta tgctattcta ggtgactatt 112140 aattttaata tatgtgtgac tttttgttgt ttttgttttg tttttattga aatttgaaga 112200 tactgagtta agatgaaagt cctaaagttc ttcaatcact tttctgaaat ctagacctcc 112260 aaatttgccc tttcataaag tttaccacta gacttaacaa aacactctaa gtgttcacca 112320 ttagtgatgt aaatctaaaa tactatatac ttctttcttc tttgtgtgtg ttttttttgt 112380 ttttgttttt gtgtttttgg agacggggtc aggctctgtt gcccgggctg tagtgcagtg 112440 gcatgatcgc ggctcactgc aacctaactc tcccaggttc aagcaattct cctggcttag 112500 cctcccaagt agctgggact acaggtgcat gccaccacac ctggctaatt ttttgtattt 112560 tagtagacac agggttccac catgtcaccc aggctggtct tgaactcgtg agctcaagca 112620 atctgcccgc cttggccttc caatgttttc ttttttaaca atttacaaat gtacagtgat 112680 tacacttcgt ttctattttt gaaacttttt tcaccttcct tcctagaagg ggaaacctat 112740 taatagttct agaaatctca atgcctacct catcctttag tctttattaa tttgtttttt 112800 ctaaatgcca gggtttgaaa atcagataaa caccatctct agagatctgc tatatgttta 112860 aaaaaatgct tatacgtgag attatctaga cttcactttg aaataagaga tataaaatta 112920 tatttggtat gttcaaaggt acttgtattc aattaaaaaa aaatagggtc ttgccctgtc 112980 acccaggctg gcgtgcagtg gcatgatcat agctcactgc agccttgaac tactgggctc 113040 aagtgatccc ttcctcagcc tcctcagtag cttggagtac agatgtgtat cacctgacca 113100 gctaattttt aaaaatattt tgtagggaca gggtctcact ttgctgccta ggtggatctt 113160 gaactactag cttcaagcaa tccttccacc ttggtctccc aaatttctgg gattacaggc 113220 atgagctatc acacctagcc tctatttgaa gttgtattct agagtcttgt agaattagaa 113280 aacttttatc tagataaata gaggtcattg tagaaatatt tgtatgcaat ctgccttgtt 113340 tggatgaagt tttcttctct tgcatttgta acaattcaca agaaatatct atctgtctat 113400 caaaatctgg cagagacaca atgaaaaaag aaaactttaa gctaacatcc ctgatgaata 113460 tagacacaaa aatcctcaac aaaatactag caaattgaac ccagcagcac atccaaaaag 113520 ctaatccacc atgatcaagt aggctttatt cctaggatgc aaggttggtt caacatatac 113580 atatcaatag atgtgattca tcacataaac agaactaaaa acaaaaaacc acatgatcat 113640 cttaattaag atgcggaaaa ggctttcaat aaaattcaac atctcttcat gttaaaaacc 113700 ctcaacaaat taggccaaag cataagagcc atctataacc aactcacagc caacatcata 113760 ctgaggaggc aaaagatgaa agcattctcc ctaagaactg aaacgaaaca agggtgctca 113820 ctcttaccac tcctactcaa cataatgctg gaagtcctag ccagagcaac caggcaggag 113880 aaagaaataa aaggcatcca aatacgaaga gaggaagtca aactatctct ctttgaaaat 113940 gatatgattt tatacctaga aaacaaaacc ccacagtctc ttcccaaagg ctcctagatc 114000 aaataaacaa cttcaggaaa gtttcaggat gaaaaattaa tgtacaaaaa tcagtagcat 114060 ttccatacac caataacatc caagctgaga gccaagtcaa taatgcaatc tcattcacga 114120 tagccacgaa aagtataaaa tacctagtaa cacagctaac cagggagatg aaagatctct 114180 acaacaagaa ttatgaaaca ctgatgaaag aaatcagaga tggcacacac aaatagaaaa 114240 acattccatg ctcatgggta ggaagaatta atattgttaa aatgactatg ccacccaaag 114300 caatttacag attcaatgct atttctatca aactaccaat gtcatttttc acagaattag 114360 aaaaactatt tgaaaattca tataaaaccc aaaaagatcc tgactagcca aagcaatcct 114420 aaacaaaaag aacaatgtct gaggcatcac accacccaac tataatacaa gtctacagta 114480 accaaaacag catagtactg gcacaaaaac agcttatcca ccacaatcaa gtgggcttca 114540 tccctgggat gcaaggctgg ttcaatatac gcaaatcaat aaatgtaatc cagcatataa 114600 acagagccaa agacaaaaac cacatgatta tctcaataga tgcagaaaaa gcctttgaca 114660 aaattcaaca acccttcatg ctaaaaactc tcaataaatt aggtattgat gggacgtatc 114720 tcaaaataat aagagctatc tatgacaaac ccacagccaa tatcatactg aatgggcaaa 114780 aactggaagc attccctttg aaaacgggca caaggcaggg atgccctctc tcaccactcc 114840 tattcaacat agtgttggaa gttctggcca gggcaattag gcaggagaag gaaataaagg 114900 gtattcaatt aggaaaagag gaagtcaaat tgtccctgtt tgcagacgac atgattgtat 114960 atctagaaaa ccccattgtc tcagcccaaa atctccttaa gctgataagc aacttcagca 115020 aagtctcagg atacaaaatc aatgtacaaa aatcacaagc attcttatac accaacaaca 115080 gacaaacaga gagccaaatc atgagtgaac tcccattcac aattgcttca aagagaataa 115140 aatacctagg aatccaactt acaagggatg tgaaggacct cttcaaggag aactacaaac 115200 cactgctcaa ggaaataaaa gaggatacaa acaaatggaa gaacattcca tgctcatggg 115260 tgggaagaat caatatcgtg aaaatggcca tactgcccaa ggtaatttac agattcaatg 115320 ccatccccat caagctacca atgcctttct tcacagaatt ggaaaaaact actttaaagt 115380 tcatatggaa ccaaaaaaga gcccgcatcg ccaaggcaat cctaagccaa aagaacaaag 115440 ctggaggcat cacactacct gacttcaaac tatactacaa ggctacagta acccaaacag 115500 catggtactg gtaccaaaac agagatatag atcaatggaa cagaacagag ccctcagaaa 115560 taacgccaca tatctacaac catctgatct ttgacaaacc tgagaaaaac aagcaatggg 115620 gaaaggattc cctatttaat aaatggtgct gggaaaactg gctagccata tgtagaaagc 115680 tgaaactgga tcccttcctt acaccttata caaaaatcaa ttcaagatgg attaaagatt 115740 taaacgttag acctaaaacc ataaaaaccc tagaagaaaa cctaggcatt accattcagg 115800 acataggcat gggcaaggac ctcatgtcca aaacaccaaa agcaatggca acaaaagaca 115860 aaattgacaa atgggatcta attaaactaa agagcttctg cacagcaaaa gaactaccat 115920 cagagtgaac aggcaaccta caaaatggga gaaaattttc acaacctact catctgacaa 115980 agggctaata tccagaatct acaatgaact caaacaaatt tacaagaaaa aaacaacccc 116040 atcaaaaagt gggcaaagga catgaacaga cacttctcaa aagaagacat ttatgcagcc 116100 aaaaaacaca tgaaaaaatg ctcatcatca ctggccatca gagaaatgca aatcaaaacc 116160 acaatgagat accatctcac accagttaga atggcaatca ttaaaaagtc aggaaacaac 116220 aggtgctgga gaggatgtgg agaaatagga acacttttac actgttggtg ggactgtaaa 116280 ctagttcaac cattgtggaa gtcagtgtgg cgattcctca gggatctaga actagaaata 116340 ccatttgacc cagccatccc attactgggt atatacccaa aggactataa atcatgctgc 116400 tataaagaca catgcacacg tatgtttatt gcggcattat tcacaatagc aaagacttgg 116460 aaccaaccca aatgtccaac aatgatagac tggattaaga aaatgtggca catatacact 116520 atggaatact atgcagccat aaaaaatgat gagttcatgt cctttgtagg gacatggatg 116580 caattggaaa tcatcattct ctgtaaacta tcgcaagaac aaaaaaccaa acaccgcata 116640 ttctcactca taggtgggaa ttgaacaatg agatcacatg gacacaggaa ggggaatatc 116700 acactctggg gactgtggtg gggtgggggg aggggggagg gatagcattg ggagatatac 116760 ctaatgctgg atgacgagtt agtgggtgca gcgcaccagc atggcacatg tatacatatg 116820 taactaacct gcacaatgtg cacatgtacc ctaaaactta aagtataatt aaaaaaaaaa 116880 aaaaacagac acatagacca atgaaacaga agagagaacc cagaaataaa gtcacacaca 116940 tacgacgttc tgatcttgaa cacaatcgat aatagcaagc aaggcagaaa agactccctg 117000 ttaaataaac tgtgctggga taactggcta accatacgca gaagattgaa actggacccc 117060 ttcctttcac catatacaaa aatcagttca agatggatta aagacttaaa tgtaagacct 117120 aaaactctaa accctagaag aaaactaaga aatacctcga ttaaggcctt ggcaaagatt 117180 tcatgacaaa gtctccaaaa gcaattgcaa caaaaccaaa aatagacaag tgggacctaa 117240 ttaaaataaa gagcatctgc acaacaaaaa caaaactatc aatagagtaa acagacaacc 117300 agcagaatgg gagaaaatat ttgcaaacca tgcatatgat gaaggtctaa tatccagtat 117360 ctataaggaa cttacataaa tcaacaagtg aaaaacaacc ccatttaaaa atgggcaaag 117420 aattaaaaag acagttctca aaagaataca tacacgtgac caacaagcat atgaaaaaat 117480 gctcaacatc atgaatcatt agagaaatga aaatcaaaac cacaatgaga taccatctca 117540 caccagtcag aatgacaatt tttaaaaagt catgggcggg gcgcggtgac tcgcgcctgc 117600 aatcccagca ctttgggagg ttgaggcggg cggatcacga ggtcaggata tcgagaccat 117660 cctgactaac acggtgaaac cccatttcta ctaaaaatac aaaaaattag ccgggtgtgg 117720 tggtgggcgc ctgtagtccc agctactcag gaggctgagg caggagaatg gcgtgaaccc 117780 aggaggcgga gcttggagtg agccgagatc gctccacagc actccattcc agcctgggcg 117840 acagagtaag attacatctc aaaaaaaaaa aaaagaaaaa aaagaaaaaa aaaaagtcag 117900 aaaataacag atgttggcaa ggttgtgggg aaaagggaac acttatacac tggtggtgag 117960 aatggatatt agttcagcca ctgtggaagg cagtttgaag atttctcaga ataaatgaaa 118020 acagaactac catttgaccc agcaatccca atactgggta tatatccaaa ggactataaa 118080 tcattctacc aaaaagacac atgcacgcat atgttcattg cagcactatt cacaatagca 118140 atggcatgca atcaacctag atgtccatta atggctgact ggataaagaa aatgtggtac 118200 atatatgcta gggaacatta cacagccata aataagaaca aaagcatgtc ctttgaagca 118260 acatgggtgc ttcagagaaa ataccattca acaaagtttc agtaatattc gagctatttt 118320 gtggataatg cacaactttt gtaccttaag gcattgttca attctgttta agaataaatt 118380 gtttttgagc tgcctattag atttcaagcc tgactttaga tttgggagat atatatatat 118440 atatatgacg gtttctgttc tagaggagca gacagtctgt taggccagac acagttgaat 118500 agcaatatat tataatattg aggaagtagg ctgggcgcgg tggctcacgc ctgtaatccc 118560 agcactttgg gaagccaagg agggcggatc acctgaggcc aggagctcaa gaccagtctg 118620 gccaacatgg caaaacctgg tctttactga aaacacaaaa tttagccggg catggtggca 118680 ggcacctgtg gtcccagcta ctcgggagac tgaggcagga gaatcacttg aacccgggag 118740 gtggaggttg cagtgagccg agttcgcacc gctgcactcc agcctgggtg acaaagcaag 118800 actctgtctt aaataaataa ataaataaat aaataaataa ataaataaat aaatactgag 118860 gaagtataac aataagttat ctttgagaca cggaggaagc acagaagagg atataatcac 118920 ttcttttggg atatgaggag ggggaaaaat gttaagagaa gcttcctaag taggtgagag 118980 ctgaaatggg ttttgtaaaa taaaaggaaa ttcaccagga agataaaggt aaaggactga 119040 ggacatgtga ggcatgtaaa attaatatga tcttttagtc acttagaaaa aataccataa 119100 agaacactaa tagtgtttaa aagcatctac ccagtgccaa gaactgcatt atgtattggt 119160 gaacataact ttagacttta ccatacaacg tgaaaatata tattattatc actattttac 119220 agatgaagca ataaaagtca gaaaaaatgt agctaattaa agtgatactg tgtatagcta 119280 gagcagtgta tagctagagc tgatttgtct gactctagcc ctagtttctt tccattatat 119340 caatttcctg gaaatgtatc tctgttcatg gcatagtgcc tgacactatg cttattaata 119400 tcttttgaat aaaagaacca ctgagtgatt tgaaataaaa ctaaatttag ttagttaatt 119460 ttattggtgg tatatagaga tagtaggaaa aataattgaa aagagacata aacagatttg 119520 ccaatacttt ctaagaaaaa ttatggaact agagtttagt caaaatgaat gctttcattg 119580 ttagaattca actttaatct ttgcagaata caaacaaaga cccattttct agaagaagta 119640 acagggaaga gagagtaaga aagagataat gatgaacatt gtctaatgtt acagcataat 119700 ctagtaaggt aagaacagaa gagagttcat tgacttacca acatagttgt ccctaatcac 119760 ctctgtgaac ctagagtgct acgatataat aatgattgtg gtggtttaaa aagtaaatgg 119820 ggctgggcat ggtggctcac atctgtaatc ccatcacttt ggaaggctga ggcaggtgta 119880 ttgcttgagc tcacaagctc gacaccagcc tgggcaacat ggcaaaaccc cgtctctaca 119940 aaaaatacaa aaattaacca ggcatggtgg tgcgtttgtg tagttccagc tacttggaag 120000 gctgaggtgg ggggattgct tgagcctggg aagtggaggc tgcatgagcc aaggtggcac 120060 cactgcactc caacctgcgt gacagagcca gatcttgtct caaaaaaata aaaaaattaa 120120 ggtacatttt atatatgaga ctatgagacc gccaaatgat atttctcagc caacagcctt 120180 cacagacatt tgtcttagag ccgatttggc tactttgtgt tgccagtatg ctgttgtaag 120240 aaagcacagg aatgcttgta aagaagaaaa gaattggtat catggtcctg aaaaaagtta 120300 tttcctcaag gaataaaaat agcaaaagaa atgacgtaat ttctcagctt ctgatatgtt 120360 tcaaataacc tcagtgaagt cctaggggaa atagcttata tcatatgtct tactccttag 120420 gatttttgct atagaggaaa aagtgtgaag ttttcttaat ttaatgtttt atacatattt 120480 gcttgctgta cctggacctt acaaagtgga tactctttag aaagtgatga atattttcac 120540 ttttaaaagg tttcagagtt taaaaaggtt aaaaagaatc attcataaaa gtttaaaaac 120600 aacttcatca agggtttccc ttttgccaag ttataagttt aaaatgagag aatgaatttg 120660 gttattaaca gggttaccac caggcctgaa tgtaaattaa acctttgcca atagaagtga 120720 aacagaaaga atcaaccaac aattttatga attacagacc tcatacacat taaaacttct 120780 acatatgtag ttatgcttca gtgaaaccct ttacattgta gttatgcttc agtgaaaccc 120840 tttatattaa aataatcatc acgtatttga ccatatgaaa atagtttaca tctaccacat 120900 ttggtttatc ttggccaaaa acaattaatc cttagaaaat ctactatatg aataactcaa 120960 taataatcaa agcatttgaa ttagaaatag gatcaaacac acttttttga atgaatgcct 121020 aatttttatt tctcagtgga aatgctagag catatccaat attcactagt gaaaaaggct 121080 attttccatg aagcccatga gaagatgaca taagttaaac ttgtccaatt ccttttcagg 121140 gatagcatca agaaattgtc tttaccccta taaactgaag catttgaaaa tcagtaatat 121200 taactgagca aaataacttg tggcaacagg tatcagtctg ggacacaatc aagatacaga 121260 aaccgggccg ggcgcggtgg ctcacgcctg taatcccagc actttgggag gccgaggcgg 121320 gtggatcacg aggtcaggag atcgagacca tcctggctaa cacggtgaaa acccgtctct 121380 actaaaaata caaaaaatga gccgggctgg gtggcaagtg cctgtagtcc cagctactca 121440 ggaggctaag gcaggagaat ggcgtgaacc tggaaagcgg agcttgcagt gagcccagat 121500 tgcgccactg tgctccagcc tgggcgatag agcgagactc cgtctcaaaa caaaaacaaa 121560 aacaaacaaa aaaagataca gaaaccacat gctaatttaa acagagaaag tttaatatat 121620 gaagaattat taagtactga taggagagta accataaaga tgtaagagaa tctaaagggt 121680 atcctggagc taaggtagag gactcaaaga agagtgaact ggaaggattt cccatcccaa 121740 ggttggggtc caaacttcat tgggaaaagt gtggtggaag ccctctttct ctacagcaga 121800 atagtttgct ggggtgtcct ggccggagct ctggtccaca gttgggctac tgttgggcaa 121860 gcagaaacaa ttctttaggg cacaggtgag ctaaggttgg tgggtgggcc ttcagaagga 121920 gtgcggcact gaagtgagga tgtgtctgtg ttggcagtgt gcggtgtcag tgctgggaga 121980 actgtggcaa agtggtcact aggcccttat atagaggctg tgaagtcacc aacagactgc 122040 cccatctggg catgtggctg gggaaaaaca ccaccagatg tcattacaca agcacgttgc 122100 caatggtcca ttgctaatgg tccacattgc taatgatcga agtaaaatca aaatgtagca 122160 ttagaaccag gaagagaagc cccttcctcc tgcagtgacc cttcactgcc ctctactgac 122220 aaagagtaac gttatgctca cggtctaaga aaaatgcttt aagtgcccaa tacactattt 122280 ctggttagct accaaagaga gctaagaggc aatacactgg taactgtcat gtcttgtaca 122340 tgaatatcat tattcatgtt tttttaaaat cacagactat acttcttaac agctacatac 122400 attttattta tattcatcag aaacttactg cttattcttt gcccttaact acttgtatag 122460 accaacatgg aaccaaattt gctgtcatat aggctgttga tctcttcatc cactagcact 122520 tttctgaaac aaaaagcaag taatcttcga attcacataa gcatttatct gcaactctgg 122580 tgttacttga cgactgactt ctacctccca gtatatttgc ttgtgaatat gtcttgtttt 122640 ttgctttagt ccataagcac cttgagagca gcatttacct ttgcattctt cactgtatcg 122700 tgcaaagtac tttacccata acagtcacac aatagttgct gaattaatta ataaaatatt 122760 tggaataaca acacctaaga gtgagaggtt acaaaacacg atagttcaaa attcaacagt 122820 tataaaaaaa aatcaaaagt taaaatacag aatatgttac agtattgaac attgtatggt 122880 aaatgtaatt tactggaaag tatgaatttt atagtgatca catacttttc ttaatattta 122940 gatatctgac acatgtaaag tagcaatagt tcttattctg aaccattctt gaataaataa 123000 gaagagaaca caacttggct aacaattttt atcaattcag ctttgggtgc taacataatt 123060 taattgggaa agaataatca tttcagcaac tagtactaga aaaaccagat atccacatgc 123120 aaaaggaagg atttgaaact gtggataaca atgtacaaag attaattcaa aattaatcat 123180 aaatttaaac gtaagaacta aaactataat tctttaaaaa tatgagtaaa tatggtgcac 123240 atacataagg taataatttc ttggctgcaa caccaaatgc ataagtggtc aaaagagaac 123300 attgataaat tgtacttcat aaaaaatcat ttgcccttca aaagacaaca tcaaaaaatg 123360 aagacaaccc acagattgaa agaacgtatt tgcaaatcat atatctgata agcgattgta 123420 tctggcatat atatatatat tttaaaactc ttacaagtca ataataaaaa accccaaaga 123480 acctaactat aaaaataggc agaagatttg ggtagatact tgtccaaaga agataaatga 123540 ctaatcaacg agcacatcag atgctcaaca tcattaatca tgaaggaaat gcaaataaaa 123600 aacccaatga gacatcacgt cacacacact ggaatgacta taataataat aaaaaaaaca 123660 gataatcaca agtgttggga aggatataga gaaactggaa ccctcatata ttgttagtag 123720 gaatgtaaaa tggtacagcc atttggaaat acactggcag tgtcttacaa tgttaaacat 123780 agattcatta tatgacccag taatttcatt cctaggtatc taatcaaggt aaatgaaaac 123840 atgtatccat atgaagactt atatggacat gttcatagca gccttattaa caatagccca 123900 aaagtggaaa gcacccaaat gtccattagc tggtaaatgg ataaacaaaa tgtggtatat 123960 ccatataagg gagtatgatt ggtcaattaa aatgaatgaa tactgaaaca tgctgttagg 124020 tgagtgaatc tcaaagatat tatgttaagt gaaagaagaa agtcacaaaa gatgacacat 124080 tgcatgattc tattcatata aaatgtctag aataagcaaa tgtacagaga cagcaaatag 124140 tgattgccta ggactgggag tgggaataga gagtgactac aagtgggcat caagtttctt 124200 tttagctcaa tggaaatgtt ctaaaatgag attgtaatga ttgctgcaca actctataaa 124260 tatacaaaaa agcactgaac taacaaggag ctaaaactac aatgataatc atgtaagcag 124320 tgataattat ttgattccct tctttttctg tttgaatcag aatgccttga caatttttta 124380 ttcttttctc ttctatagga tttcaaggag tttagaactt tacagaaata ataacaaaaa 124440 ttacagcatt tgattaataa atacatcttt tagtaatttt ctttttgcct aaagtcaaga 124500 ataattgttc atcttagtat gtttattaac tactcttggt gttatgttgg gcgttataat 124560 aaagaaaaat ctttgtttca aaatttaggt tggaattttg gatcctactc tgactaacta 124620 ggtacactac tgaatttaca tcaagataac agtacagata gataagaaca ttgatttcct 124680 taagatcagt aatttgaagc ttaaacatag tatgcaacac attgagagtc tcaaagaagt 124740 aacaagtgcc atctttagaa aatattttat atacttggtg tggtcttatc ataagaagta 124800 tatacataca taccttgaca tattgtactt tgctttattg tgcttcacag atacagtttt 124860 tcacaaattg aaagtttgtg gcaaccctac atccagcaag tcaattttgg tgccattttt 124920 ccaacagcat gtgctcactt cgtgtatctg tgtcacattt tggtaattct tgcaatattt 124980 caaacttttt cactattatt atatctgtta tggtgacctg tgatcagtaa tatttaatgt 125040 cactttagta attgcttggg gatggcaaga actgcaccca aataagagtg aacttaattg 125100 gtgttacgtc tgctctgact gctccaccaa catgctgttc ccgtctctct tcctctcctt 125160 gggcttccca gttccttgag acacaagaat attgaaatta ttccaatcaa taaccctact 125220 atgtgggtgg tggggaggtg ggaatgatta atgggtataa aaatgtagtt agatagaata 125280 agatccagaa atgtagttaa atagaataag atctagtaac acaacagtta tcacagtcaa 125340 caataattta ttctatattg aaaaatagct aaaagagtat aattggaatg tttgtaacac 125400 aaagtaatga taaatgcttg aggggacaca taccccattt actctcatgt gattattgca 125460 tatgatacgc ctgtatcaaa acatctcatg taacccataa aggtatacac ctactatgta 125520 gccatacaaa taaaaaaaat ttttttttaa tccctacaat ggcctttaag tgttcaagtc 125580 aaaggaagaa ttgaatgttt ctcactttaa attaaaagct agaaataatt aagctttgtg 125640 aggaagacat gttgaaacct agataggcca aatgctaggc ctcatgaacc aaacagttag 125700 ccgagttgtg aatgaaaaag aaatattctt aaatattctt gaaggaaatt aaaagtgcta 125760 ctccagtgaa cacaaaaatg ataagaaagt aaaatggctt tattgctgat atgaagaaag 125820 tctgaacaaa agattgaacc agccataaca ttcccttgag ccaaagccta attcagagca 125880 aggctctaac tctcttgaac tctgtgaagg ctgagagagg taagaaagct acagaagaaa 125940 agtttgaagt tagcagagtt tggtttatga ggtttaagga aagaagctgc ctccataaaa 126000 ttaaagtgca aggttaagca gtaggtactg gtgtagaagc tgcagcaagt tatccagaag 126060 atctagctaa gatcattgat atggtttggc tatgtcccca cccaaatctc atcttgaatt 126120 gtagctccca taattcccac atgtcatggg aggaacccag tgggaggtaa ttgaatcatg 126180 ggggcaggtc cttctcatgc tgatcttgtg gtagtgaata agtctcagga gatctgatgg 126240 ttttataaag gggagttgct ctacacaaac tttctttgcc tgccaccatg taaaacatcc 126300 ctttgctcct ccttcatctt ccaccatgat tgtttgaggc ctccctagcc atgtggaact 126360 gtgagtccgt taaactgctt tcctttataa attagccagt ctcgggtatg tctttattag 126420 tagggtgaga acagactaat acaatcattg atgaaggtga ctacactaaa caacagattt 126480 tcaatataga tgaaacagcc ttatattaaa agaagatgcc atctaggact ttcatagcta 126540 gagaggagaa gtcaatgctt ggctttaaag cttcacagaa taggttcagt ctcttgttag 126600 gagctaatgt caccagtgac tttaagttga agccaatttt catttactag tcaaaaaaat 126660 cctagggccc ttaagaagta tgctaaatat actctgcctg tgctctataa gtagaacagc 126720 aaagcctgaa tggcagcaca tctgtttaca gcatgcttta ttgaatgttt taagcctgct 126780 attgagacct actgctcaga aaaaaaaaaa agattccatt caaaatatta ccgctgactg 126840 acaatgttgc aaagagctct gatggagatg tacaaggaga ttaatgttat tttcatgcct 126900 gatagcacaa cacgcactct gcagctcatg gattgaggaa taatttttat tttcaagtct 126960 tattatttaa gacatacatt ttataagact atagctgcta tagagagtga ttcctctgat 127020 ggatctgagc aaagtaaatt gaaaatcatc tggataaaat tcaccatcct agatcccatt 127080 aagaacattt gtaattcatg ggaggaggta aaaatatcca tatgaacagg agtttggaag 127140 aaatcgattc caactttcat ggatgacttt gaggggtaca agattcagtg gaagaagtaa 127200 ctgtaaatgt ggcagaaata gcaagagaac tagaattaga atgcagcctg aagatgtgac 127260 tgaattgctg caatgtcatg ataaaacctt aagagaggag gagttgcttc ttatagacga 127320 gcaaagaaag tgatttcttg aaatagaacc tactcctggt gaagatgctg aggacattgt 127380 tgaaatgaca aaaaaggatt tagatattac ataaatttat ttgataaagc agtggcaggg 127440 cttgaaagca ttgactccaa ttttgaaaca agttatactg tgggtaaaat gctatcaaac 127500 agcatcacat gctacagagg aatcttttgt gaaaggaaga tcaatcaacg tggcaaactt 127560 cattgttgtt ttattgtaag aaattgtcac agtcatctca accttcagca actaccaccc 127620 tgatcagtca gcatccatca acatcaaagc gagactctcc accagcaaaa agattatatg 127680 actcactgaa ggctcagatg actgttagca ttttttagca ataaagcatt tttaaattaa 127740 ggtatgcact ttttttcaac ataatactat cacataccta atagactata gtatggtgta 127800 aacataactt ttatatgcac tgggaaatca aaacacttgt gtgactcact ttattgcaat 127860 attggctttt ttgtggtggg ctggaaccaa atgtgtaata tctctgaggt gtgcctgtat 127920 ttggtcttag ttcttgctgc ctggcacaga gctcctataa cccttgttat ttcctgatta 127980 atattggtga tagcagcatc tttcttatat ttggccttag ttccattttc tgacataaga 128040 gcttctataa tctttagaat ctctggagtg cctttttgta tgctaatgag atgacaagtg 128100 gctgagggcc cctacatagc ttcaggattg aggctagtca ctagaaagac ctgcatctgc 128160 aagggatggg ctaggggttg aagattaagc taatcaccaa tggtcaatga tttaatcaat 128220 tatgcctaca taatgagacc tccataaaaa ctctaaatta tggagtttgg atagcttctc 128280 ctaccctata ctttctgcta tatgtctctt ccaggctgtt cctttacaat aaactggaaa 128340 tagtaagctc ttaaattctg tgagctgttg tagcacatta ttgaactgga ggatttatag 128400 ctggtcagtc agaagttcca gaggcctggg tcttgcaact gatgtttgaa gtggggcagt 128460 tttgtgagac tgagccattg acttgtggta tctgaggata atgccaagtt attattgaat 128520 tgaattgtgg gacactcaac tggctgtcag acaattgagt ggtgagggaa aaacagaaac 128580 aaaaacaaaa acaaaacgac ccacatattt gatgtcagaa gtggtgtggt taaaacagta 128640 gtacttggct tttttttaaa tttagaatct aagtacttaa gagtagatat cttggcacct 128700 agtattaaat atactaggtt ctcaatacat attgttaaat gaatgactag taaatgaaaa 128760 aagaatgaga aaattatttc ttgctctgac caacttcctg actgttttac tctaagtccc 128820 aataaatatg aatattacca taatagctaa aagaatgcta ttgattaaaa tgtttcctgt 128880 catttgtctt ttagcttgaa caaccgatat atatactaat cataaatata aaataacagg 128940 tgtgctataa ttttaaacag ctacttttaa agttttgaaa ttgtagatta ccctctgaga 129000 attagatgca tacaccaagg ttattgctag agggcaagaa ttactacact ttaagataaa 129060 acacaatgga gacttggaag ggtagtaggt gcaaggtggg tggatgatag gaggttgctt 129120 ggtggataca atgcacattg ctccagtgat ggatgcactg aaggccgtaa cttcaccaaa 129180 atgcaatata tcaatgtagc aaaattgcac ttgtacccca caaatataca aaaattttta 129240 aaattgataa aataataatt aaaattgttt ttcacactct aatgttacct tggtttgaga 129300 tataatgtga tccttggatc tcatggagaa tattaataat tctctttctt agataataac 129360 aaacctgtaa ctattcatat ttgaaaaata aataagaact ttaaaactgt taccacttcc 129420 ttacctccct tccagctatc atattattta gtatgctcat caaagacaga ttttaatgta 129480 tattttaaat ttcttaaaaa gtttgtatca agaactctaa gaagaaagtt gttttctgct 129540 gtaaagtggt agaaaaatca gaaattagtt aaacaatgca atgattttca gagagttgtt 129600 caatgttaat atataaatta ttttgtgcct gtttctgaaa gcaggaaaac atctgagagt 129660 attaaagaac tagcccaaat gggttcattt tgaacaaatg atgagagaag gagagagtga 129720 atgaaagtag tgagccaagc tctttgtgtg attcctactc ccagtgagga ccagaaggga 129780 gaatcaaaaa gaaagagaac aagcccagtg caagaaacca tgcactggaa ttgtttcctt 129840 cagatttaag tgttaattga ctatatcttg tgtgtactgc atggactttg ttggccttct 129900 gttttcctta atcaagaaaa ccctaagttt tgggatctgt ttatacaaca gatgatcttt 129960 tggctattaa taaaaatgta aaattcttgg tatttttaat gtgttattta aatttacttc 130020 aaaagtaatg atgcaactaa aatgaaataa aatttccatg attatcagaa taattaaata 130080 aatgtaaaac tacaaggaaa tattatgaag ccattaatat tatacttttg aactattctg 130140 atggcattaa aaaatgttta agatgtaata tgtgctacaa aattgaaaac accataggaa 130200 tcccattatt caaacaggaa gagaaatggt ttagagcaaa atattaacat gttaaaagca 130260 atattttatt attgtgggga aaatcacata gattatgaga tcacaaatat tattttcttc 130320 tttatgcttt tctaaatatt ctgttttcta taatatcaat gcattccata actataaaat 130380 atagtacttg aataatttgc taataattag actcaagcaa agaccaaaga atgcctcaaa 130440 atgagctagg cacggtagct cacgcctgta actttggaag gtcgaaacag gtggatcacc 130500 tgaggtcagg agttcaagac cagcctggtc aacatgatga aaccccatct ctactaaaaa 130560 tacaaaaaat tagctgggca tggtggcgca tgcttgtagt ccccgccact tggggggctg 130620 agacaggaga attgcttgaa cccaggaagt ggaggttgca gtgagccgag attgcttcat 130680 tgcactccag cagcctggga aacaagagcg aaactccgtc taaaacaaac aaacaaaaaa 130740 gaatacctca aaatgataaa aggagaagta atcaaatttc tcagacactg aataagtaaa 130800 aacagctaac agtaataatt tgaagaaaaa atgcattcag aattactttg aaaagcagtg 130860 cttaatcata gtatatataa gtagttcaat actcatagta tatatgagtt tagaatagga 130920 gtttgggact tgcataagaa ataaaagaat tatttaaatt attatatgct tcaagcatat 130980 ttctacaaaa acagtatttg cgaaagcatc ctataaaatg taaaactgtc aggtattaat 131040 attaaaggta accctaaaaa tgtttttgtt ttgtttcatt ttcatttaac aatttctatt 131100 gagaacctag acaccgaaaa cggaagtagg cagtggcaat gagacttagt cacatcagac 131160 aatatgctgc accatattgc aaagaaggta cagtatagca gaggaagaca ggggaataag 131220 cacaataaag tgcagtggga gagatgatag aaatgtatac aggacctagg cacaacacaa 131280 aaggaaatta atcatacttg gggaagaaga ggtcgtggct attcaccaaa taaagaagca 131340 gtagcaaaga cctagagata gaaacagctt taggtcttca cagaaatgca attagttctt 131400 tctgaaggac taatggtaag gtagatcgac catggggtaa gaaataaacc tggacagctc 131460 atgaaagcca gccatgctga ataactgaat agcttttact ccaggatata acttacagtc 131520 ttaaaaagta gagatgtggc ccacatgttt gaaaggtcac tggtggtagt atggagatca 131580 ggttctaatt gagggaaggg agtgggtgaa catttagaaa aagaccaata gaaacttctt 131640 acattggttt aggtgaggaa agatgaaagt cctaacaaga gtattagaac atttatattt 131700 tataatcctc tgatttgctt tgcaacaatt tttactcact ttatacagaa cttactgaac 131760 taaactgata tgtgcagctc atattacagt aatgaaaaat gtactaactt gtgtaatgtg 131820 acaaatatct tctctatcct gcataattct gggggactca attatctgca ttataataat 131880 ctcaactaat acagtgcaac aaacttaatc tgaataattt atcagataat ctgataattc 131940 atcagattca gtgtcccaga atctgatgaa ttatcaaatt catcagattc agtgtcccag 132000 aatctgatga attatcaaat tcatccttgt cataattttt ttgtctcaag actccttttg 132060 attgttaata ttattgagga aacaaaaaat tcttctttat aatgagttca atgtattgcc 132120 atttaccatg ttagaaagca gaaaaatcac aagcacatca attaataaat ttataaatta 132180 taatcataaa tcacatgtca acaaaataaa tttcaagtga aaataaccat atttctaaaa 132240 gaaaaagatc taatgggatg agtgcttggc taagttatgc aggtcttcaa aatattggaa 132300 gatttcatta ttcatctgtt aatattacca ctaatcacat cagaaaccct gtaagttttg 132360 agaagctgtt gagctcatgg tggcagatgc atctttttca aaataataat tttctcttga 132420 aaggccaaat tttgtcactg acaacaaata ttgtcaaatg tatttttaaa atgacagtct 132480 ccatttattt tcaaaaattt gtcttttcaa tatctgtttg aataatcaca atttgtctct 132540 cagtcatttt ttcaaataaa aatagtattc tatggaagta cagctagttt agcttgcaac 132600 tcaaacaact acacaagtgc tttaccttaa gacaaccagc attattgttg atatacagca 132660 gatgttaatc atgtatactt tccatttctt catgtatact gaatattaaa aatatgtgta 132720 cttaatggta tagattaaat aaaattaatt tctagtgttt cgtcaaagac attcttttag 132780 tgcaactggc tttaatttta ttcatttatt tatttactta tttttactgg gaatgaatta 132840 cagtgaagaa tacaatgaca gtatagtttg ttgtcactgt cttgataagt gttaaggcta 132900 ggggtttcat tgttcttcca aatgtcaaca cagtgaaaaa ggtaaataat gtttttgtat 132960 cattatgaaa atagtttgga cctgatgaat catttaaaaa gtctcaaggg aatgcaagag 133020 catctgtgga ccacattttg aaaataactg ctaaaatcac attaagaatt ttttggccgg 133080 gcacggaggt tcatgcctgt aatcccagca ctttgggagg ccaaggcagg cggatcacga 133140 gatcaggagt tcagcctggc caacatagaa aaattagctg ggtgtggtag tgtgcgcctg 133200 taatcccagc tactcaggag gctgaggcag gagaatcgct tgaacccagg aggcggagat 133260 tgcagtgagc cgagatcctg ccattgcact ccagcctggg caatagagtg agactctgtc 133320 tcaaaaaaaa aaattttttt tttgattttt tggattatat tctatatgca ttaaagacta 133380 tgaacattct gagaacatga ctgtgaaaag ttttttttat atgttactga atggaaggag 133440 ggttagaaat cagcagagta tgcaaaaaca gagtaaaaca aaatgcctag gaatgaaaaa 133500 aaaaagagag agagagagag agagtcaggg agagtaagat aaagtttggt cccagagaag 133560 atacagtcaa gattccactt tttgctattc cacagagatt tcaggaagaa aaatcacact 133620 cctattttct ttttctttgc ttactgattt ctatttagtt tctttttttt tttttttttt 133680 tttttttttt gagaaagcgt ctcactctct tgcgcaggct ggagtgcagt ggctagattc 133740 ttcttgagta tgctcaaact tcctttttgg aatgtcttcc aaaggcactc ttgccttcat 133800 ttgtacaagt tgattgaccc tttaaaggcc ttaaatatta ttgtgcgacc tcacagactc 133860 ctcaaatcac ctgaaacctg aaatgctgag gcccaggtgg cactgaaatg atggtattct 133920 agacctgaca ccggactgtt ttctccttgg ttttgtccca acacactgac atacatagcc 133980 caaaatacta ctggcctttt taagtggcat atcacattcc agggtaatat caaaactgct 134040 gcctggtagc atttgtgaag tctcaaagta actctttcca ggattttcaa atccactgaa 134100 tttcttagat tgaaatatgt atgtgacaga attctcttag ctttctttcc tctatgaata 134160 tgtaattgga aactctgaga tccggtttct catctttatt ggattttttc tttaatctta 134220 aaattatgaa tatttgcttt acaataatct agataaggag tccccaacct ttttggcacc 134280 agggactggt tttgtggaag acagttgttc cacggacatt gtggggagtg ggggctggca 134340 ttagaatctc ataaggagca cacaacctag atcctgtgca tgcacagttc acaatagggt 134400 ttgtgctcct atgagaatct aatgccgcca ctgatctgac aggaggcgga gctcaggctg 134460 taatgctccc tggcccactg ctcacctcct actgtgcgac ccagttccta acaggccagg 134520 gaccagtact ggtccgtggc ccagggtttg gggaccctta atctgatgtt actaagttac 134580 atcattaata atctatttct cctcacacag atttctttcc tcacatcctc aacacatata 134640 atttcacatc tccaaatgca gcattcccta ataattaccc ttcttactcc attctgccac 134700 ctctggctca ttttcacttg ccattccatt tgataatcta gtaacttcat tttgccaact 134760 tgatgaattt ggttctaagt agtttaaaaa tttaaggaca tactatgtca gtatttacag 134820 gtgcttctta tttattcttc agtattctca aatgttcaat ttgaggtcaa gttttgctaa 134880 aaacaactca ttgcaaatag tagatgtttt ataaatataa gataaatttc ttaaaattcg 134940 tgctgagttc taaagagaaa acttaggtta ccaagtaaca tgattttcag aacaccacca 135000 atttgctatt tcaagtctaa ttttatatta gaccgattcc caaagctttt ccattgttac 135060 aaaattttca aaatactgta cttttattat acaaggtttg tggcctagtt ttattaatat 135120 tccaaaagac aaaatattca aacattcaat tgtttcatca ataatttaaa ctaaatttac 135180 tattttgatt aaagatacaa tgagtatctt tgcatgaaat agattactaa attctatttg 135240 aaaactaatg tacactttta ttctagtttt taaggcaaca tatgtttatt ttgaacttta 135300 ttttaagaaa acataccaaa acaatgccaa attgtttggt aagaaacaat accaaagcat 135360 ttgaaaaaat aaattattaa caataataat tttgttgtgt aaaattgtga gttatttcat 135420 cattttatta atttatattt cccttttgct ttatgtatta cttttgcttt atgtattact 135480 tttgtcataa gaaaaataag atgtaatatt ctatttaaat tttttttttg ttttatgcac 135540 tttatgttcc ttttttatgt actttatgtt ccttttcctt tatgtattac ttttattata 135600 agaaaaaata agatgtaata ttctattttt aaaacaaaaa ctttataaag aagaaaacag 135660 aaatcctaat tctataaacc agagataact attatattat cttcagggct ttttctaagg 135720 aaaaacatgt ttgttttttt tccgtaattg gggccatcct agatatatat gtttgtaagg 135780 tactttttaa tatactatta taacctgggc aattttatat agaattaaat attcattgaa 135840 acattatgtt taatggtact ataatatttc atcatttgcc tagactatga tttatttagc 135900 cattctttca accttccagc attgtgtatg tagactgttt tcttttttct tttctctttt 135960 tttttttttt tttttttttt ttttgagaca gagtcttgct ctgtcatcca gacgccaggc 136020 cggagtgcag tggcatgatc tcggcttgct gcaacctcca cctcccgggt tcaagtgact 136080 ctcctggctc agcctcctga gtagctggga ctgcaggtgc acaccaccat gcctggctaa 136140 tttttttgta tttttagtag agacggggtt tcaccatgtt ggccaggctg gtcccaaact 136200 cctgacctca ggtgatctgc ccaccttggc cttccaaagt gctggaatta caggtttgag 136260 ccactgtatc tggcctatgt agactattaa tctctccaat tttgtttggg ttgaattagt 136320 tttcctatat ggggatagtt tggtggaaat gtcagtcaag gaactgttag ttaagtttac 136380 tcttaactaa aaggatcaga ttcatgaccc aaacttgacc aaccagatgt ttacttcctg 136440 gaattttggt gttaaacatg aatgtcagga aaaaaaagaa aaaaaaaaaa aaagaaaaag 136500 aaagaaagac aaagagcctg aaagcagttg agctgattca ttctagatta cagcacctta 136560 cagaaaccac caaaagtcta ccaactgggc tatctgctct tatagttttc tctgctcctg 136620 gcatttttca gtctagattg tagctatccc ttaactctgt gaactataat atcttttgaa 136680 gacattgctt ttatacttaa attaacctga gtcagtttca gttacttatt gtaatacttt 136740 aatttttttt taccaattcc ccatgaattc ctaattttat atccttttct gtcactttcc 136800 tcactgaaat aaatgagcat cttaattctt atcacagatc atgaatgtaa atgtgacatt 136860 ataggcacag cagtggaatc agtgtcacca tcattttatt tctgccccca ctttgttagt 136920 catcatgcct gtaattacaa acctaattaa ttgcctttat tagaatctta acacatacac 136980 agataactca ttattatcca gtaggaggag ggtatgaata atgaaaatcc atcatttata 137040 aaataaccac aacagtttca tcaacaacaa aaaaatatca atttaacctt ctttgcttat 137100 gattttagta gtcataagta ttgccagaga caactgttag aggctgaatt gtatcctccc 137160 caaatccata tgttggagtc tcaaactccg gtacctcaga atgtgactgt gttaggagtt 137220 agagcctttg aagaagtggt ttagtgaaat gagactttta gggtgaacca caatccaata 137280 tgacttgtgt ccttaaaaga agatgaaatt tagacagaaa agagacacca ggaatgcaca 137340 tgcacagagg aaaagacaga catcagcaag ccaaggagac gggctttaga agacaccaaa 137400 cttcccagta ccttgttctt ggacttcgag cctccagaac tgtgataaat actgttattt 137460 aagccaccct gtctgtggta ctttgtcatg gtagcccaag ttaactaata cagaaaccaa 137520 ccctatttga atggcacacc tctatctcaa gttcagtagt ttccccaatg gtatctgtga 137580 aacaaaagca tactagcaac atatattaca aagaacatgg ataatatttg tgtaactttg 137640 ggaaagcatg tgcaatacag taaatatgtt tctttggaat aaatataacc tttccctgga 137700 aatatttgct cattatctcc ttaaattttc agtggagtca caaatgaata tgtttccaat 137760 aatgagaaga aacattttgt tgtgaagtta gatcaataaa gtgtttaata gttaagggta 137820 tatggatcag ttttctgatt ctttaaagtt atgtggattc tcaagaacaa agaatctcac 137880 tgaccttttc ttaaaagata tatccctagt acccactgta agaaataatt gatgctaaaa 137940 tcataaacgc atggacaaca atgttaataa gacaattcac cggggaaaga attgtctttt 138000 caacacgtgg tgctgggaca actagatatg aacaaacaaa agagtaatgc tgaaccccta 138060 cctcacatta tatgcaaaaa gttgactcag aatgaatcct agatctaaat gcaagagcta 138120 aaattataca actagttgaa aaataataga agtaaatttt tatgacctca gattaggcaa 138180 cggtttctta tacatgagac taaaagcaca agtgacaaaa gaaaaaagtt agagtagatt 138240 cttcatcaaa attaaatcta agtttgtagg tagagcacca aaggagaaac aggcaatatg 138300 ataaggcaaa gacttttgac catttacaga gaaaagctaa aatgtcaggt tgattctaag 138360 ttagaagaga agcaaattca cattttctag agaagaacta cagtgtccat aggtaactga 138420 gaatgagggg aagcaaatag tgaaaaaaat ataaaaagat aaaccattgg aatatgagtc 138480 ttgaaggaat aaaaatatgg taacaaaagt tttaacatag atgaaaatga aagctgatgt 138540 ttatcaaatt attttgaaat cacattccta ctcattcatt tgcaaaaaaa aaaaaaaaaa 138600 aaaaaaaaaa aaaaaaaaaa aagatttgtt caaatccctc caagcagctc ctgtgtcctg 138660 gccactatgg gggatgtaaa cactggtttt catgcttagt gtctctttct tgcctgcacc 138720 tggtcagtgt atcatttctg gaggaagaaa aactgactgg gtgactatat cattctaacc 138780 aatgatctca ttcaaacaat ttttttttca tcaaatagta ccttttcaat attttttaat 138840 ttttaaaaaa gtttttagac aagagcagta gtgagaagag gggaaagcgt agaacaagga 138900 gtttgatctg taactgactg tgaacaatca actgagataa ctcactacct ttggatcagt 138960 tcttttcaac atttttgagg caattttttt gcattctagg aactgcaaca ttttttcaga 139020 gaactttaca aactctcaaa actttttttt gtgaaaatga ctgatttatg ttttttttaa 139080 acctaataac ttgttaacat tgaatgtttt aaatttattt gacataactc tttgatttgt 139140 ttttttaaaa gtcgggggca gttagagccc taagcccaat ctctgagatt ccacagatct 139200 ggctgcacac ctctatggtg ctatttctgt tcgtttcttt tactttcagg atcacccaca 139260 aggtttgtgc cactcttcat acctgtgagg cacttcaccc tttagcacct ttgattcaat 139320 ccatcattgg cctcattaga tttctgctta aaaaaacttt ttctccacct ctttcattat 139380 tttctgtttg catgcccctc tcatcctcac tatctcttta tcttgcagta tttttcttca 139440 aagaacttac atttactgac atttctttgc acattgattt gcctactgtc caactctatc 139500 accagactga aagctgcatg tgggtaggaa ttttgcttta ttcaccacat tcctgcactt 139560 agaacgcaga cccttctatc ttctattgta caggagagct tttttttttt taatttttta 139620 acaaatagcc cggtgtgatg gctcactcct gtaatcccag cactttggga ggctgaggca 139680 ggcagatcac ttgaggtcag gagatcgaga ctagccgggc caacatagtg aaaccccatc 139740 tctacaaaat acaaaaatta gccaggcatg gtgacactcg cctgtagtcc cagctactgg 139800 ggaggctgag gcaggagaat cacttcaacc cgggaggcag aaattgcagt gagccaagaa 139860 cgtgccactg cactgcagcc tgggtgacag agtgagactc tgtctcaaaa aaacaacaaa 139920 caaacaaaca aacaaatgga gtggatttgg gtaatcattc taaaccaaac tgtttttgga 139980 attttggcat gtcagaaagc agatgaatta cagctcacat gtacgactgc acccaacttc 140040 agtcctgagt ctcttggcta agctgtagct ctaccatcac atggatgatg agcaaacatc 140100 aagaacacag acgccatggc cacggtgtgg ctggactgct tggattctgc cacttactaa 140160 ctgtataacc cagcaagtta attgaacctc actgtgcctt ggttttgtca cctgtaaaat 140220 taacaatagt atctacctca taggattaaa tgagatcata tttgcaaagt actgcttagg 140280 atagtggctg gcacagagta aatgctatat gtttttgata aataaaacaa ttaataaatg 140340 gaaatctagg aatgtggaca aaatttaaaa gttggaaaag caaactttgg ggcagcttgg 140400 ggaattctgt cacaacttat ttttctgatc acaagtgcaa tgagaataaa tttcttccca 140460 ccctacccta aactaatgca atctcaattg agcggtggaa catgcttcat tcactaatta 140520 gaatttaaaa aggaagtgat aacctcacgg agcacagccc cattgaccct gagggtgact 140580 atacaggacc ttcaattgct gattctctcc catccttctc tgggatctgt ttctcccacc 140640 ctccccattc tgaggtagct ggaagagagt aggctttgtg ccctttggcg agtacaggga 140700 gaaaatagta ggttcagcct ctccaactgc ccagggagaa agcaatacct ttcaaggtcc 140760 ccaggctaaa ttttggaggg atgcttttgt gtgtcactgt caggctcaca ccgacataaa 140820 cccttgagaa atgcctggtt ggtgacgtcc tagaggtaac accaagcaag ccccagattt 140880 tctcttcttc gtcagcaatt cccagatgag gtgctcttgt gtttaccctc tctgattgtc 140940 tggattccct gatagtaccc tctatacaag gaactagaat gtttcttact ggattcctct 141000 gttggtggtg atagagttta ctttgggtat ctagtcggtc tggttgcccc tggtatctct 141060 ggttggtaca acagaatcct gactgagctc cttagtgcct tcttgaatac tgtataatta 141120 actaggcctc caattgtgcc ccgccttgcc ccagcccata gatggacaat ccctcctgcc 141180 atgtcttaaa gagaaattac cataataaat gactctccag acagcacatt tcccagcaag 141240 agggggcatg taaaccaagt ctattagtat tggcagcaaa atccaatgtg ttattgttac 141300 cagtatgaac actctgggta tcctggcctc ctatatagat atttgaaaca aaacagacaa 141360 acaatgtgaa ggaaggagga aaaacagcca cacaaatgag ttacagtgag tttaatgaaa 141420 actaattcca ttgctgggtc catgtgatat aaccagccac ttgtgctctg ttctagtggt 141480 ttataatgtt acctcaccct ctccaagaaa ttggtttccc gtaaatctct gtggccattc 141540 attcctgtct acacattatg ttcctaaaat agacaccagc taaaaatctc ttccaggagc 141600 tttgtgaagg aaggcctaaa ttgcaaaact cctcctagaa gagagatgtg attttgtaat 141660 tgcttcattg caattacaaa agcaacaatc ataaaagaga gttttaaaag agtttttcac 141720 cacagtcatt ctcctgaaat gcacagctga gggaaagaag aatgtcagat gccccgcgaa 141780 cgtgcagaag ctcccagttg catcaccctg gcgtgccagg tattgcagca aataggaaag 141840 gtaagctacc cacttctctg ggcaggagaa actaaagcag gaatcaccaa cctcagcatg 141900 gaattttcct atttctgtct ggcaacatcc tcttgggatg atttaaagtg ctttttggag 141960 aaatatgttc tgttactata ctagcgcatc agaaatacca cgtgaacctg taaatccata 142020 gaagaagaag acacatttta taggtgtgat agcaacagca attggcaatt tgcaagtttg 142080 ctactgcact cagaaatatt tagtcacatg cacatattga cagtaatata ccctgccttg 142140 acttaattgt tgcattggac aggtgaaaag cacataccca ccactccaga ccgatttgtt 142200 aacaatcacc agtgagtaat caaagagaac aaaaagaaat gagaagtaaa tgcagcaagt 142260 gggtcgggtc tttaaacaca tacctcaaac aggtaggagt caggaaatcc atgatagcaa 142320 agacatttgg acaagcctca cctccactca gaaataattc ttatgctgtt ctgaaaagca 142380 agacggttca cactaggaac tgagcagtat ctgcagtatc attgctggtt gtgacctctg 142440 tctaagtaaa agtaagtcaa tgtttcctat ttggcattgg atagaaaagg ggactcttta 142500 ccactctgct caagctcttt tttagtgtgg ctcaatagga gttggcagag gtggggggcg 142560 gaaatcattg ccccttcctt gttcaaggca tgaggcattt cttctcaaaa gcccagcctc 142620 agcctcagga agctgaatac ccctgcaatg ctaggctcca gcagcagccc cgctgccttc 142680 tttcttcctg tggagttaaa actgagatct aatttttgct ccgtccttaa gaacaatatg 142740 acctctattc ccagccagct agtccacttc caaagcacca gtgaaggagg gggcttcaac 142800 aggatcaaaa gggaccttga ataggatgaa ggcaagcaaa ggcaagaact ggccagatgc 142860 caagctattt caggccaaag aatcccatct tctatcaaaa tgctgaactg caaaacaaac 142920 ctgatttcag ttcatggaag gttgagagag gaggggggag gggaggggag gagaagagga 142980 ggagagggag gagggggaca gttggtctga atacacatac aaaaatggac ttcctgctct 143040 gcccaaactg aatttccatg gactcttttt ccaaaggaat aactggaatg aataaactta 143100 aaatcaagat gaaacaatta gatggcttac ctgattaaaa ggaaaattat ccatctgcag 143160 tgaggaacag catcacccaa agacgagatg ataacaatgt gccttcagtt gcaattgttc 143220 agattccttc ttgcaaaagg tgtcaaagta tttacaaggg ctgcagtctc actggggcag 143280 aacacacaga cacacaaaca cacacaaacg cacacataca cacatgcacc agagacctct 143340 gcagtatcct ctcggcttca tcctcgcctc actctatggt acctaataca aatcagcaaa 143400 tagcttgttt caaaaaaaaa aaaaaaaagt caagacagca ccttacatta catcgccatc 143460 tagtggctaa atattaaaca ctttctcaca atccagattt atgatttctt cctcaacctc 143520 ttttctctca gccttttttc ctttcttctc tgtaatctcc cagtattgct tctccttgct 143580 tctctttcat tccctattgc tatataatat catgaaccta atgactcaaa gaggaaaagg 143640 tttgaaagta aatatagcta ttttcaagta gtacttgaaa aactttagca ttattttagt 143700 ttgaaactgt tactttattc ctaatatgaa tcattgttat ctataaaaat gatatatctt 143760 ataaataaaa ctgtcttttt attccaccag gaaacaatca ggtggccctt tattacagat 143820 ctatggcttc acatttttct gttttaatat tgtgttttag gattaggttt catattatag 143880 tgaacagctc agagtcacaa aatgtgagtt ttacttcaac actgatgaac acatgccttt 143940 aacaaagcca ctgaagtctt ctatggacat ttacattctt actatcttca tctgtaatta 144000 cagattaaac aagactttca acccactctc aatttctatg gttttactat attttactcc 144060 aatgttttcc catcttgtgg acacagccta aagcttaatt ataataacac attttaataa 144120 gcaaatatat atagaaagag agtccaattg cctattaccc aaagatagaa ttataaaaac 144180 catgaatatc agttttttct aagacaataa aaatccatgc caaactaatt ataactcttg 144240 gaactgagag tagagctttt tatgttatat attgtattct aaaatggaat cagccttaaa 144300 cattcagtca tacataaaat cacgattatg tgtagattag tcattggaag taaatatttc 144360 atcctcatta tttttctttt gccatctaac acacttatta caatcattgc atgtgtttta 144420 tcatttatca atataacctt caatatttaa tccttctctt ccttattaca ggatggtgag 144480 ataaatacta ttaatgttat tatattataa ttattcctat ttatacttga gaacactgaa 144540 gctttctgag ccttactgag gtttattcaa gaccacatag cttgcaaagc aataaaacta 144600 aggctgttgg tcccaagagc ccaaagaata atccactgtt ctttgcaaca tacctaaaag 144660 ttcaccattt tttcctgttc tagaatcaca gaaaagtaat tttgatttct atgtttacaa 144720 aacatttact agcccttaat tatggaccaa tgggtccatc ttgtggatcc atctttttat 144780 ctataaaaga aagaaattaa gtaagataat ttcctgttcc agctcaaaaa ctctatccag 144840 tgctttccca aaagccagtt ggagtagcat gaacacattc atttgaagtt actcaatgtc 144900 tgggaaatga tgttgcccag tatctggtag agtcagggca aagttgaaag aagatgagga 144960 gacaggtgat caacaactgg taaacgattg ccaagatgtt agagatgaaa agagagtggg 145020 aactgcatga actaacaggc aattttttta gaataataca ttccatatga atagtactta 145080 gagattagat atgtaaaaac acaaaataag aacatacctg gccacatgtt ttaatgaatt 145140 ctaattgcat attataggtg ccaatttttc tgagtgtctg ctcttaacaa ttcccccaat 145200 agttcttctc ccctgatcct tagtggtaaa cctaccctct tgctacagag gactggagca 145260 agagagggta tctacgcagc tgacctggtc aaagagagcc actacatgtg attctggcag 145320 ctatggagtc agctttccct caccatgggg actcaggacc aggtggacca ggatactgaa 145380 atagcagcca gccacacaga tgtggaggaa gaagtgacaa aagacagaga cagactgttt 145440 ccatctccag tctactcaag atccaaacac tttcttgatg ttgagtccca tgataaactc 145500 aaactccatg tttgcttaag tgaacttggt ttctgttgaa ctatggagtc ctaaccactt 145560 cattagcttc aagaaagttg ccagtactgc atctatcaag tattattcat attctgggca 145620 tctgacactt catttattca cttcttcatg cacctgatat atgccaggca cttttccaga 145680 tacttaagta acatcggcaa acaaaccaga tcaaaaccct ccctttgtgg agtttacatt 145740 gacatgtcag tcatatggaa aggcacaacg cattcagtgt gcacactacc tttcttccgc 145800 ctccatgtct ttgttcacaa ccttcacttc tcttggcaga cctttcatcc atctacacat 145860 agcaaattcg gcggatattt taaatgtctg ggtcaaatat tctctcttct ccaacgtctt 145920 ttctattttc tcagcagata gaattctttt ttcttttgtt aattatagaa caattttatg 145980 ttgtatctta tgaaacatgg tcatttgaca agttgaaagc attgagcata aggagataaa 146040 tgactattct catacagact cctagaaaag gccaatatcc caagcatggc ccaaagagta 146100 ctattaacta acaactcatc attctgtaca cagatacttc attcgtcaga gctgaagcag 146160 ttttacagta ttagtaactt taaatcttcc atgtttcaga ctgagcataa aggcaaaata 146220 tgagattttt attaaattag tgtaatatgc acttaaaatc acatatttat tttttaaagt 146280 tagcagaaga tattaaaaca aaactctgtg ctaccctatg tcactactac acttatccca 146340 tttgaccttg ttctaagagt tttatatatg tatcttattt ggctcccaga atgtaaactc 146400 cctgtggaac cagctttgca ttttatttat ttttttgtag attaatttat tgagagataa 146460 ttttgtctct ttctcactgt tacgtttcca acttcaaaaa atgaaaaact aatcttcctc 146520 tgcccccgtt ggtaaagtta gccattccag gaaccccttt gtaatcttgt ttcagaagct 146580 ggaaaaaatt agctgcctac ttcctaggtg acaatacttc aatctgtaat gcatgaacct 146640 gctaaacagg ctgagggggc atggctgtgg cttttttatg agagttccta acaaggaaaa 146700 gagaatgaag gcgtaagatg tcatttagtc tttgtaagac tccgtctctg taagactccg 146760 tctctgtcct gtgaatgtgg ttgttacttt gttatagctc tgtcagttgc actgctcagt 146820 gccaaaacat aaaagggaat attataatgg gacataatct ctgtcaatag attttgggta 146880 ttaaagagag cgtgaggtca ctcaggtgga aaaagctggg ccaggtaatt ttgtctgtta 146940 gttttacgac ataaaggaga gtctctcgat gccattagat cttgaaagag ttcaaagaga 147000 gaactatctc attatcagaa ggctgaggaa ttagtgtaat tagtatctga atattcttta 147060 atattttctt gcatagaaaa taaaggtaat tggttatcaa aaatattctt tcaaatgtgt 147120 atctcctgga gttgtggagt tctgaaactt taaccagctg ccttatgaag agaatttatt 147180 aattaacttt atgcctgcca aggagaagga aaccattctt aatttttagc caaaaatttc 147240 ccaaagtgat gaccaaatca ttatgttttg agttccagat tcccttgttt agagttataa 147300 atgacatttg agttttaagg cagaaatgtt tctaaattcc cctgtcattt gtttgggaat 147360 ctatagtcac tgagcaacat gaagctgggt ctcccctctc ttcccaccgc aggaaaggaa 147420 ttggaggctg gaggcgaact tgagtacctt gaggtggtat cccaaaggag atggtggtga 147480 caacagacaa gtctagatgt tagcaggtct tctgatgaag tcggggagtg atcccaacac 147540 agatagcaaa tgctagagtt tggatttaaa ctcagacctt aagattttag atctacagga 147600 ccactgtatc actacaaatc ctgactttgc ccccttttga ttggaataat cagataaagc 147660 acactactga tgtgatcctt ggtaaatgta atttactact taagtacttt gcttttgtag 147720 atgtcaattt cctagtggtt tttttttttc ttttggtaaa tgcagcattc tgcaaaaatc 147780 tactaccaat tccttgctct cacaaagcat tcaccaacac tgtgccacta ttttagaaat 147840 agaaaccata tcctagccga aaatgataaa ctcatatatt tccttttgag attaacctgc 147900 ccttttgaaa gggagtcaga aatgaatgtg aaatttattt gctattagac aaataaatgc 147960 agaaactgca attaagaact ctcttttagg actagagcca actagttttt ctgcaagttt 148020 aaagttacaa ttttttgatg gcaagaattg gccaactgat ttcaaaatat cttataggta 148080 ctaaagtgga cttttgaaac tctggtaaag tccatacatt ccataaatta aaaaaataat 148140 aatcagccat ttttttcaaa tatgatataa aaatatctga gggctcctcc cctccccgca 148200 actggaattc actgaatcag agctgctata ggcttgcatt ttttgatgca cagataacca 148260 gtttttaaat cacttgtaat ataatgaaca taaataattg aatttttttt tcttacagat 148320 ttgattctga agtatttttg aagtatcttt agaaccaatg tgcttgtggg cacacattac 148380 actatttaaa attttattaa aagtatttta aaaatcctta gagagagaat gccagttatc 148440 tctctctctt tctggtagtg gagaagaaaa aatagtatag gcttttctta actcaccaca 148500 atgcagtaat taaaagcaaa agagaaagga gggaagttgt gggattatga tggagataat 148560 cagattcccc agttgccctc tgccttccct gctatcgaga caacgcacag aagccagaat 148620 tatgtctgca ggtgattatt tcagggaagc agttactcct tgttggaaga ttcactgcaa 148680 tttcctttca attacatagg cagacattgg tgttggagag ggaaataaca atattcctaa 148740 accaaataag tagcttttat aaacaagaca gaataataca tgaacctgat ttctcaaagg 148800 gaaattaagt atatgaatgt caatcatctg atgagattag cattacaata taggttcaga 148860 atgagtatta aatcacaaaa ttacttttta tcacttgatg taatagcatt attcctctga 148920 ttatatcacc aactgaacag cacttcaaaa attactatag tgctctgtat atatctttaa 148980 ttttaaatcc tttattattt gggggcctgg tttatttttg atcttttctt ctttagctaa 149040 cgtgtaagaa gacattatta atatttagtg aagatgacac taaatgtcgt ttttcaaaac 149100 aacaaactct gccttttcct aaacaagcag ggagccatta tgccttcact gttccgcttc 149160 ctttgtttcc tctgttttca ggaccttctc ttctttgacc gcatcttcct ccaccctcta 149220 tcggtgcacc tctccacggt ctgaccccac tcaataatct ctttgaaagt aagaactatg 149280 acttattttt tttgtcattg ttccccaaac atatcccaag tctgtggtag aattaaggta 149340 gtttctggag agaacctgat aacatctgct gagtattgat gaataaaaat tccgtaatag 149400 acttccaaca aaaccctgga gtagaataaa ataactttgt aaacctcata aaaaagaatg 149460 tcaatttaca taaatcatta ccattgcttt atcgataggg ttttgctaat cattgagaaa 149520 ttgtggagct ggaaaagtct cagagataaa ccaggcaagt gttcttattt tggatatgag 149580 gaaactgatg ccaagagagg tgcagtgact tgtccaaggt cacatagata gttttatacc 149640 acaaaggtcc attcaagttt tcccacagtt taactctaaa ggaaattaat attgagtaag 149700 gtacatcagc acataagaag caaaatggaa gtgagtgaag tatttctaga tatgccacaa 149760 ttgattttca ctcatgtttt gacagagaga tggatgtgat gaagggtatg aatgcagtta 149820 ctgtttaaga aggtgatgga ctaaccaaca ttggttttag caaagaataa agaaagtgac 149880 tgtccttcaa tctagctcca catgcggttc ttaaatatta accacaaagt actcaagccc 149940 aagggcacga gctctgggta tgcagagtgt agcattgaca gctttcagga atgcaggccc 150000 aaagacagct ccagaaaata tccaggaagc aaactatctt gaagttctat actttctttg 150060 aaatgccaag atgtaatcta aaaatatgtg ttctactttt ttagtctaat aaaccacatt 150120 tatatgatgg ttatctgtca tatggggaga caaaattcaa catttcacat gcctgagctt 150180 tatacccctc ctttaaatgt atcaagattt cataaagctt tggttcttca gaaaagatca 150240 aggtacatca caatatttaa agcattatct ccatatctat tgccacagga ggataaagag 150300 aaaataaaca taaatgcaaa taatgaaaat gcctgagcaa tcataaagaa tgaagttact 150360 gtgtggattc tattctgtgt ttatgtgttc tttcctttgc tcttaagtca gttaaacata 150420 atgcttgggt tctttcctga tttatttcat tcagcaatcc cccctacccc ccgacatccc 150480 ttgcaaagat gaatcaacaa aagctattac caagaacaat atgattgatt acttattgga 150540 actcgaatac caattttcca cttaagtata tctttatatc aatcacctca cttgcctacc 150600 tattgaagag tttcaattag atttttttaa taaagaggac tttctttact ctaaaggata 150660 tagctgatat ttatgaagac aacgctttat ttacagaata aaactgaact ttgccataac 150720 ttagcataag caaatatgta gtttctgttt ccctaaagaa ttcctgtcaa catctttttc 150780 ctttcatgtt caaaggcaga aagtcattga ctttaccagg agcacagcaa agccatctgt 150840 aaagtataca agtgtcgcta gaattaggtg ctaccatatt tcttggggaa attaacattt 150900 ttgacacatc tgtatgcagt tccaatcttc ggatatcaat ttacaaactc acataaatta 150960 catttggtta catcttttct ttttgtttct ttccttgaga aaagcaagaa ttctactcta 151020 ggccaaataa tggacagaaa tcattagggt ccactccagg gactgaggcc ctttagaaga 151080 gattggcaag tgactaggga aaaggtacat cgaaggtcag aaaataatga catttagcct 151140 agttctcctc gtgattcctt ggaaattttg gggcccatga gctcagttgc tgcttctggg 151200 attgccccta ttcatatcaa atagcagaga actgagatgt cttacccaca cctgagaaga 151260 ttcggatgtg agcatgggat agaggtgcta ggcagcggca ctttcatgcc taagtgcagt 151320 ctctcatacc tgttcatctg cagtggcatg aaaggcaaac agattcttct gctcattatg 151380 ggttgttgaa atgacagaac cactttgtct caacattttc tatgacactt gatacataag 151440 gaagctcaga gactaaagtc cttgtttcca tgttgcacta ggtctttttg aaagtctctt 151500 ttacattctg attgctatca tgacatcaaa gtcacctgta ttcctcatct ttgtggggaa 151560 gagcaggcta aataaagtag gtaaggacac cttctgagtc tgcacccctt taattgacac 151620 ataggggatg tgacccctga cgtttctgct tcccttattc tttctgcaac taagcaaaca 151680 tagaatgtgg attttcccat gctcttagca aggatgaaac tcagcgatca tttgctctac 151740 ttcacatggt agttgtttct aagattacat atcatatata tgcatatata tatatgttat 151800 gttatgctac acacacacaa ctgctaatga gtgttctctc tccccttttc ttgtccctct 151860 gctctctagg acagcagtag ctttatatgt atctctatct gccctaagtc tcctctcttg 151920 ggcatcacaa acagagttac ccttccatga accatttgtt gctttaaaat tatacctcag 151980 atgcagtcat ggtcctagca gaaagtagat ggtacattca aaatggttaa aataaaaata 152040 attatggaga aactattgac caagtgggtt aagatggttg atgagtgccc aggaactagc 152100 aatagagaga gccaatgcca ttccaggcaa gagtgaaagt ggcaccagat tccggtgaga 152160 gctagagctt tagaagaccc aactgagagg tttaactaaa gaggaatgca gctgcttttt 152220 taagctagga agtgaggtgt ggtcggggag actctccaat tttctgctaa tgcctgtctt 152280 gggctgcatt caaagccaac ggatgaagga ccccaagttt ctcaatccct ggaaagtgga 152340 cttgaaagtc tttccctcta cttgtccatt attccacttc taacctacat tttaatactc 152400 ccaacactct cttccctggt ctgcattcct tggagtccag tgctcctgct agtagccctt 152460 cttccagggc tccagcattt gttgggctct gggaatgttt tttccaggtt ggcagttgtg 152520 aagggctggt gggaactggg gaaaataaca atgtgtctca tcttatctct aaaaacatct 152580 ctttttcttt gtttaaaaag caaaacacat gtgtctaaaa tattttacag agatgaacaa 152640 aaatctttat gataaaagat tctatttaat accctaaccc ttaatacagt gcctagtata 152700 tggtagtgta tgatatggtt tggctgtgtc cccactcaaa tctcatcttg aattgtaact 152760 cccacaattc ccatatgtag taggaggaac ctggtgggag gtaattgaat catggtggcg 152820 agtctttcct gtgttgttct catgatagtg cataagtctc atcagatatg atggctttaa 152880 aaatgggatt ttgctgacac agctctcttt ttgcctgctg ccatccatgt gagatgtgac 152940 ttgctcctcg ttgccttctg ccatgattgt gaagcctccc cagccatttg gaactgtaag 153000 ttcaataaac ctctttcttt tgtaaattgt catgtctcag gtatgtcatt atcagcagct 153060 tgaaaatgga ctactcagta aattggtact gggagtgggg cactgctaaa aagattccca 153120 aaaatgtgga agccactttg gaactgggta acaggcagag gttggaacaa tttggagggc 153180 tcagaagaag aaaggaaaat gtgggaaagt ttggaactcc ctagagactt gttgaatggc 153240 tttgaccaaa atgctgataa tgatatgaac aacgaaatcc aggctgaggt gatctcagat 153300 ggagatgaat aacttgttgg gaactggagc aaaggtgact cttgttatat tttagcaaag 153360 agactggtgg cattttgtcc ctgccctaga catttgtgga actttgaact tgggagagat 153420 gatttagggt atgtggtgga agaaatttct aagtggcaaa gcattcaagg ggtgacttgg 153480 gtgctattaa aggcattcaa ttttaaaagg gaaacagagc ataaaagttt ggaaaatttg 153540 cagcctgaca atgcaataga aaagaaaatc ccattttctg aggagaaagt caagctagct 153600 gcagaaattt gcataagcaa tgaggatctg aatgttaatc cccaagacaa tgaagaaaat 153660 gtctccaggg cattcagagg ccttcatagc agctcctccc atcacaagcc tggaggccta 153720 ggatgaaaat gtggtttcat gggccaggcc cagagttccc atgctgtatg cagcctaggg 153780 actttgtgcc ctttgcctca gccattccag ctatggctga aaggggccaa catagtgcat 153840 gggtcatagc ttcagagggt gcaagcctca agccttggca gctcccacgt ggtgttgagc 153900 cggcaagtgc acagaagtca aaaactgggg tttgagaacc tctgcctaga tttcagaaga 153960 tgtatggaaa cgcctggatg cccagcaaaa gtttgctgca ggggtggggc cctcatggag 154020 aacctctgtt aaggcagtat ggaagggaaa tgtggggtca gagcccccac acagattccc 154080 tactagtgta ccacttggtg gagctatgag aagagggtca ccatcctcca gaccccagaa 154140 tggtagatcc actgacagct tgcactgtgt tcctggaaaa gccacactta atgccagcct 154200 gtgaaagcaa ctaggaggga gtctgtaccc tgcaaagcaa caggtgtgga gcttcccaag 154260 accatgggaa cccacctctt gcatcaacgt gacttggatg tgagacatgg aatcaaagat 154320 cattttggag cttaaagatt tgactgccct gctggatttc agacttgcac agggtctgta 154380 gttcctctgt tttggccaat ttctcccatt ttgaatggct gtatttgccc aatgcctgta 154440 ctcccattgt atctaggagg taactaactt gctattgatt ttatagcctc ataggcagaa 154500 gggacttgcc ttgagacttt ggattgtgga cttttcagtt aatgctgaaa tgagttaaga 154560 ctttggagga ctgttgggaa ggcaagattg gttttgaaat gtgaggacat gagatttggg 154620 aggggccagg agtggaatga tatggtttgg ctgtgtcccc actgaaatct catcttgaat 154680 tgtaactccc accattccca tgtgtcatgg gaggaaccca gtgggaggta attgaatcat 154740 gtgggtgggt ttttcctgtg ctgttctcat gatagtgaat aagtctcaca agatctgatg 154800 gctttaaaaa tgggagtttg cctgcaaaaa ctctcttttt gcctgctgcc atccatgtga 154860 gatgtgactt gctactcctt gcctccagca tgattgtgag gcctccccag ccacgtggaa 154920 ctatgagttc aagaaacttg tttttctttt gtaaattgcc cagtgtatta gttcattttc 154980 atgctgctga taaagacata cctgagactg ggtaatcatg gcagaagatg aaaggcacat 155040 cttacatggc agcaggcaag agagaatgag agccaagtga aaggggaaac cccttataaa 155100 accatctcgt gagacttata caccaccaca agaacagtat ggggaaaact gctcccacga 155160 ttcagttatc tctcaccagg tccctcccac aacacatggg aattatggga gctacaattc 155220 aagatgagat ttgagtgggg cacagccaaa tcatagcagg tagagactca ggaataaaca 155280 tatggatatt caagcagtac tatttttaga taaattctaa gaataatttt agaataataa 155340 taattgttgt taattttatt gaggacttaa tatattttgg gaccttcaaa cctcacaaca 155400 gtctcataaa atagttgcta ttaccatgtt atcttcatga atttataaat gaggcaactg 155460 aggctcagag tagttgagca tcttggccaa gatcacacag taacgaggtg actaagtgtg 155520 attctgaaac cagcagtgta tctccaaagt acctaatctt accataaggc catactaaaa 155580 ctctccacaa tatcacatta ttaaaattat ggtggaaagt ctctgcaatt cgagttcaca 155640 ggcaaacaaa cagaagacaa tagtctttct ttactgctaa ggattacatc acattaagct 155700 catataagga cataatgggg gagagacatt tctacaagta gctgaccgaa gatagttttt 155760 aggtgtatga tcagtctgta gcctggattc ttgtcaaaca tgttaggggg cagcatgtgg 155820 cagggtggga gggaggcaaa tggagatctt ccttcttact tgtctcagat tcttcaatct 155880 tccatagcaa gtgaaagaat ataactatgt ttggacgtac tctcaccaag ttaacaaata 155940 cactaaacac atgagtagtg aggggagaag catgcctcaa tctggcaaag cttcaatctc 156000 cagaagtcta aatttgttag aaatgaaaaa gctagcaaag cagaactgct gatcgtgaac 156060 acttaacagt aagcttcctt tggtggaagc ttcatgttgc aaacatcgta tttaattagg 156120 tgtttttttc tcagctcatt ttctaaaaac aagtgctttt cggctctgct tgatgtttgt 156180 gaagacacgg accgcgcaaa accaggatac tttcagaatt ttaaaacctt gcttctgaaa 156240 gtgtggccac atactggcag catccccact tcttgggagc ttgttgaaaa tgtggactct 156300 ttggctccac ccagaccttc taaataagaa agtgcatttt aacaagattt ccccaggtga 156360 ttctgtgcac attggtgttt gagaagccct ggctgtcaca tctggcctca gctcttaaag 156420 cctactcact tccttctgca ccttgaacat gtaaatcagc cattctgccc tgctcaccac 156480 tccccgggtg ttcccattcc cctttgcagc cctgcttgta catactattt agatacacca 156540 agcaaaccca atctactctt ctaagtcaca tttctaatgt caattgactt gagtggctct 156600 tgaagtaaaa attaactttc cagtttctct tccctcaggc ccagtctgca gtggcaatcg 156660 ctgttaattt tttttttttt atcttcttta gaattcttgt gtatatccaa gcatctgaaa 156720 tatacgtgtt ttatattttt ctttttttta taaataacat tgtaccagac accaggcatg 156780 gtgtttcaca cttgtaatcc caacaatttg ggaggctgag gtgggaggat tgcttggggc 156840 caggagttca agaccagcct gggcaacata ctgagaaccc atctccacaa atattttttt 156900 aaaaagaaag aaaaacatca cacaatatat atggctgtaa acctagttta agttacataa 156960 tttatctcta attagttcac ttattattgc ttaaaatatt ttgttctgta tatagatgga 157020 tataccaaag tttatttaat cagttctcag atgataaaca cttatgttat tttctttctt 157080 tcttcctttt cttttttttt tttctatttc aaacaatgcg gatgtataca tttctttaca 157140 attgcatttc ccacttgtgc aaattttcct ttaagatcta gtctcaggaa atggatctgt 157200 caggtggaag ggtatgtgcc ttttaaccca gtaggtatca atagatttcc ctccaaaggt 157260 gtggcaccat tttatattcc agaacagcat aagaaactgt ttccatcacc agaaattatc 157320 aaactttttt ctttgttgac tgggaagtag aatctagact gtcttaaact tatctaggaa 157380 tttctctgag gcatttatga gtagacacaa agagggtgga ggagaaagag gaggtgcatt 157440 ctaagaagag gagatacatg taggatatat gtaaagttgg gtctgtggaa gtggctagag 157500 tctggagagg taggcagaca gccagatcag aagggcctgg cacacctgct aaagagggaa 157560 aactggaacc gcattcccaa ggaatccatg aaaatatcgt gttgagaaga taaaaccaaa 157620 tagtttgctt tttatttcca caagtttgga ggagccatct gtttcttgtc agggcattga 157680 ctgataatag ttgtgtcttt ataattgggt tgttttctcc taaaactcaa tttagacaaa 157740 gtaagtgtca gtgtgggagg gttggctaat tgttaggaag caacatttgg taaatctgga 157800 ggccaaaccc aaaactttta tatttttata ttcctggttg tgcttactac tataaagtta 157860 attataatgc ttttactaga agctgtacat ttgaaatcaa aacactctat cactgctact 157920 ttcccttctc ccagcatgag gtaacaataa tattctttag gaaatttcat atggaaggtt 157980 gacacctgtt gtactttcct tacctctctg aataaaataa ttccaacaga acactgacaa 158040 cttttagaaa tccaatttca ctgtttcact tgctgatatg gtttggccgt gtccccaccc 158100 aaatctcacc ttgaattata ataatcccca tgtgtcaagg gtgaggccag gtggagatac 158160 ttgaatcacg ggggcagttt cccccatact gttctagtaa gtgaataagc ctcatgagat 158220 ctgttggttt tataaatggg agttctcctg cacaagctct cttgcctgca gccatgtaag 158280 gcgtgtcttt tcttttcctt tgtcttctgc catgattatg aggccttccc agtcatgtgg 158340 aactgtgagt ccattaaacc tctttccttt ataaattacc caatcttggg tatgtcttta 158400 ttaccagcac aaaaacggac taatacactc gttgaatata aaacagaaaa aggaatgcca 158460 ctttatcaga gagctataat ttcatttgaa acaaaacaag aaagatttat tttttcagaa 158520 ctcagcattt tttttttttt ttttgagatg gagtttcgct ctgtcgccca ggctggagtg 158580 cggtggcagg atctcggctc actgcaagct ccgcctcccg ggttcaagcc attctcctgc 158640 ctcagcctcc cgagtagctg ggactacagg cgcctgccac cacgcccggc taattttttg 158700 tatttttaat agagacgggg tttcactgtg ttagccagga tggtctcgat ctcctgacct 158760 catgatctgc ccacctcagc ctcccaaagt gctgggatta caggcatgag ccactgcgcc 158820 tggccagaac tcagcatttt tatcaaacaa attccagatc ctaagacatg tgtgactaag 158880 gatgtatttt ggggtaaatg aggaaaacaa aaatgttgag acctttactt atcttcaata 158940 atcaatgcat ctccaaaatg gcgctattaa atctaatcat cttggatttg gttgatattt 159000 ggatggtcat attgccgagc taaactcctt tacctagaat attataatta gaaaaaagtc 159060 tgaggaatca tctaattcag gctctcagtt gacaaagaat ttaccttact ttggtaaaaa 159120 tttgtttggc tttatgtgga ggtttctcaa aaaactttga ataattattt tctgaaataa 159180 tattctaaat tggaaattgg aataaaagat cattcacgtt catcttgagt attcacttta 159240 agactaaaga gggaagtgac tttgtgatcc aggtttgtga cattgtattt taaaggagga 159300 atttatattt gatcttggga acaatttttc acattcaaag tctgagaaca tctccgtatc 159360 aaacccaaag agattttctc aagtgaaata aagtgaaaca aagaaagtag cattagcagt 159420 tccgagttgc agacagttct ttttaaaatt tgttttttgg ttcttccagg cctcatttgc 159480 aagttgctac ttaattaact agggtggtta atgttaggta aagtccaaaa tgtaaaggaa 159540 ctacatagca ataacaatat ttcagtattt cttcaataaa agttactgac actctctata 159600 tgtcaagcac tggagggtgc cagtgaaaag agatggtctg ttgctatgtt ctgcattttc 159660 gttggtgaaa acagagaagt tggctgggtc atcagtgtgg tacctctggt aaagctcaag 159720 tatagggaaa tttaattcaa tctcatgttt gaattattcc ctcttaaggg ggtaataatc 159780 ctattcccat ggagtttttt gagggcacta agtgatagaa cacatgtgac tatgactagt 159840 ataataaatg atgtattaaa atcattctat aatacatata ccggaaaatt aattaagcat 159900 atgatacgaa taaatgtatg ataagtcagg taaaatgcat taatcctagg aataaaacaa 159960 agcactggta atctctctga aggtcttaga gcaggaagac tcttgagaca ggtctttata 160020 aaaaatcact tagaaattat acttaccaat gtgttcaaac tacatgaact attgagtttt 160080 gctttgtagg atagtggaac gagaagtgaa tttggcattt ggagaccttg agcctttatt 160140 ttctcactgc aaaatgacag agataatggg gcctatcttt tagagttgct atgggtctca 160200 gaaaggatca tggttttttt tttttttttg agacagagtc tcactctgtc gcccaggcta 160260 gagtgcagtg gcgtgatctc ggctcgctgc aacctccgcc tcccgggttc aagcgattct 160320 cctgcctctg ccttctgagt agcgcaccac catgcctagc taatttttgt attttttagt 160380 agagatgggg tttcaccatg ttggtcaggc tggtctcaaa ctcctgacct catgatctgc 160440 cagccttggt ctcccaaagt gttgggatta caggcgtgag ccactgcacc tggcctaagt 160500 aatttttttt tttttttttt tttttttttt tttgtggggg acagagtctc gctctgtcgt 160560 ccaggctgga gtgcagtggt gcgatctcag gatttcactg tgttagccac ctggtctcga 160620 tctcctgacc tcgtgatctg cccgcttcgg cctccccaag tgctgggatt acaggcatga 160680 gccaccactc ccggcaggga tcatgttttt aaaattactt gaaaatacat atatagtcat 160740 tcaagtatga ggtattatta ttttaacaga aatatagcta cctatatctt atattaggtt 160800 ccttaatcca catatatctc agaatagcac ctaatttgaa ttgtagaata gtatattgaa 160860 aagaatcttt aactgttgga gaaaaatttg tgtgtgtgtg tgtgtgtagg cgcacatgca 160920 tgtgtgtgag gcttgtctac ttctatcgca catatcaggt cgagaaaatg tctgtactaa 160980 attgccaagt ggtttaggta aaaattcatg ggaaggtata atttaaaatt ctgagactct 161040 agcttgtaac atttgtaatt ttaaggctaa agacatgaaa atgaacttaa attcaatatt 161100 ccttccaaca gcctatgatt ttataacttt atgattatac catatgaccc caactgcctt 161160 ctatgtatgg tgaatggttc taaattgaag gccctttatc ttctaaactc tttgatgagt 161220 ttgggcatct acgtctggat ataagagctg tggagagatg gactactttc catactaaga 161280 agagaaaaat ttggagtgtt cagatctctc agggagggga tgaggagcag agatgggatg 161340 gggaagggag aaaatgcggg tagaagccca catctttaat aaaatttatt aaattgaaaa 161400 ggtgattggt gtaggtaagt ctctgttaaa aactagggac agacagacac tgggtcactt 161460 gacagagtgg ttaggtgtag tatacatgaa accacgatgc caggacacag aggatgatgt 161520 aagactaagt ccctgataag ttgcagaagg ttttggactt ccactgactg tggtattggt 161580 agatacctga gcaagatatc tgccaacaga tatctaccaa tagatcgtca cctagatctt 161640 caagggtgca aacaggtccc accttatacc tgagttatac aagtaaaaca tgtcttcatt 161700 tatttataag ttttaaccta cctacttcca aaaggataaa tgatatattt gttgtattat 161760 ttattatgat ggaacttttc atagcggagc taatctaggt cagtggttct caaatgagga 161820 ggaggtcagt tttgcctttg gtagacaggt atcaatgtct ggaaatatct ttggtcatca 161880 caactgaggg tttctatgga cactttgtgg gtagaggcaa ggaccctgct caaaattcca 161940 caatgtctgg gacagacccc acagcgaaga atatctgacc caaatgtcaa tagtactgag 162000 ttgagaaacc ctgatgtaag ccaacctctc atcttaataa atgagaagct gaacatcaaa 162060 gagggtcagt gatatgtgcc aaatcacaca gtgaacaaac agataagtcc tctagtattt 162120 ttcccattac agtatttaac ttctaagagc taaagttcta aaatggaact gttggaaaat 162180 agaccttctt atggacatat ttagacttaa ggtatactca ataattgcat aaatctttaa 162240 aacatagtac tgcttacagt aggatatcta ggcaaagatg aacatagaaa atttaatgac 162300 aatatgtatt taactatata cagtaaaaac catttttata atatttaacc aaattacttc 162360 ccagcacagt ggttctcaga cttcagcatg cctcacagtc acctggagga aaggcttaca 162420 caaacacaga ttgccaggac ccatccctag agcttctgac tcagtaagtc tgtcatgagg 162480 cccgaaaaca tgcattccta gcaagttccc aggtagtact gatgttgctg gttaggagac 162540 cccactttga aaaccactgt cctagaattt agtaggtact tagtaaattt tggcttaata 162600 ttgtaaatat tcaaacaata taatctcacc aaaaaatgta atctcacttt aacatagatt 162660 agttaataat gttaattccc atttagagga atacaaagat atatatggta gaatcaaaac 162720 taatttaaac ctcatttaat tcaaattccc cattttaaaa tgaaaaaatt aatatatttt 162780 aagcttatta caacaaagaa gaatcccttt tagcaatagc caaaagaaac aatattaaat 162840 gcaaatcaat tatagacaat ttgaacactg acattgttat ctgaaagata tataaactca 162900 aagattataa gtacaattaa gtatgtatcc atcatttttt aacttatgag gaatagtctg 162960 aatgccaaac tgagtaaaac ctggtctgat ggggctctta tctcaagcta tgtctaggga 163020 aaatgcctat tgacttcagt aatataaaat caggccccga gggaccataa ttgtctcttt 163080 aaattatttg ggaaatcatg tacatgttta atcaactaaa tacagcatac aattgtaagt 163140 ggtatatttt catcataaat aatcaatgtg ctgctgttaa tatggttaat agaatgaaaa 163200 gtaccttcag gggaatttat tttacgatca ctcattttca ttcctttaat ttaattttta 163260 aaatgcaaga aattttagat actttaaaac tacctgttta cctagaaagt atgtgctaag 163320 taacctgcct aatgccagtc atcactgaga gacaccaaaa caaatgattg atagttaact 163380 ttccattttg ctctttgaga tcacgtagac agtttatgca gactttactt tcctaactca 163440 tgtcatcctg tccaaggtac tgaacttcac ttgccaagga cacacaggaa gataaaccct 163500 ctcaaatgtg ctacatttgt cttcaacttt ttaaatatcc atctattttt tagattagat 163560 gccatctgtt gtattatcat atctggttaa atcttattaa aattcctggc caatatatca 163620 ctctgctgcg gcaatcttac cctgctacct ctctaggctt ttctgcagca ttcaataaag 163680 agcctgctat tttaactaat tgctgaggca ggacacagtg tgagagtcta aaacagaatc 163740 agcgctatat tgtttctact tttacccata gagtgaacaa ctgttcatat caaacctgga 163800 atcatccctt caagtctcct aaacacagca cagtttgagc caatgcagtt aatccaccct 163860 ccttcagtgc tagtgtcgaa tggcgctttt gctgcagtat tcaccttgaa actaagtagg 163920 caggattcat tatttgttga agtcacctaa ctgccagttt attcttatac gatcacaaac 163980 aatcacaaca gaagacaaat acaggcatat atataactca cttacaaggg aagcaaattt 164040 gcagccagag acaagggcaa cgtaacagcc aagaactgca gtaaatctct ttgagctaat 164100 agccacctct aataatgctc tcctacaaca cctccaatca aataaattgt attcagagtt 164160 taaatatcaa atcaacattc attccttgat ggttacagat gatgtccgat aagcaaattt 164220 gaatttatga tttatttact ccttaagtgt ctcaaagcca ggattactgg aagacttact 164280 atgcttattc aagcatgctg acagaactgt aatctcagta atttctccct gcacctctca 164340 gcatgactga caggcatctg ccaagactgt agtacataaa ctgctgaaac atgcaaaaat 164400 atttaccccc aaaagatgta gtaaaagctc agcttcctcc agcttccata acccctgaag 164460 tgttaatctg gaggaacagt tccatgagtt tccacaggcc agcagtgtgt ctcctacact 164520 t 164521 <210> 2 <211> 164521 <212> RNA <213> Homo sapiens <400> 2 auaaauaaaa guugcauucc augaggagaa aacaaaaaaa cccaucacag ugaacaauug 60 aauugcuccg uggacaucau gccuuucuaa gcaagcauug aauauaggag auguauuuau 120 gauaaccaga gacagaguau guauagcuug gcuccauagg ggugguguuc ucgguuccua 180 ugucuaccuu uuguauuuuc cagcccuucc cucauaaugu uacugggaaa guuaacagcu 240 agcauaacau uuugaaaacc caaaguguuu auaucaacaa gauuauucac agucaaauuu 300 ucccauaaau aucacuggga ccuauauuuc uuuuaauuuu aaccaagagu gaagguagug 360 aguauagagc ccuggcuuua gaaacuaacc uuuaaaaaua augagauaau gacacaguga 420 auaaagaugc aucaggguug agcaaaguua uuuuuuaaga uuagaaaaac ugauuuugaa 480 aaugcaaagg cagacaaaaa ggaucaguca agagggaaag aauaaagaua gaagagaagu 540 agaacaaguc auggagcaag guaucugaga auguagaaau gaaugggaaa aauugaucuc 600 ugaaaagaua uaaaaguaug gauugaagga aggaaggaag gagagggaga gaggaaggaa 660 gggagagagg gaggaaggga gaaagggaaa gguaggaggg ggagguaaag uaagaaaaag 720 gaaggaaaaa ggaagagaau ggaaggaaag aaaaaggaag gaaaaaggaa gagaauggaa 780 ggaaagaaaa aggaagggaa gggaaggaaa agggaaggga aaagggacuu agauauuuuu 840 cacuggauag gaaagaaauu gaggaaguuu auaaugaugu ccucuugcuu guugcugagg 900 ugaggggcug aguuaucugc aaauaugagg aguguucuaa cggaaugaua aaggacucaa 960 gcaguugagu aaaaucaauu gauauugcaa auuauccacu ugugauuuua agaauuucuu 1020 ggugaugcaa uuuucccauc uauacuugau ugucuagagu auuuuccucc ucuagugccu 1080 uugcugccac acugauuaaa ucaauauuga uugacaaccu cagugggaua uuuccaugug 1140 ccaggaagaa uaguacuauc agcaguaccc aauucauggu gguuuagaaa cacauuuauu 1200 uucuuauaua auaagaaauu ccagugcaca caugaagaau augcaauuac cagacauauu 1260 ugcugucuuu agugcgacaa guuuauauag uucgaguguc 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ccuccaauca aauaaauugu auucagaguu 164160 uaaauaucaa aucaacauuc auuccuugau gguuacagau gauguccgau aagcaaauuu 164220 gaauuuauga uuuauuuacu ccuuaagugu cucaaagcca ggauuacugg aagacuuacu 164280 augcuuauuc aagcaugcug acagaacugu aaucucagua auuucucccu gcaccucuca 164340 gcaugacuga caggcaucug ccaagacugu aguacauaaa cugcugaaac augcaaaaau 164400 auuuaccccc aaaagaugua guaaaagcuc agcuuccucc agcuuccaua accccugaag 164460 uguuaaucug gaggaacagu uccaugaguu uccacaggcc agcagugugu cuccuacacu 164520 u 164521 <210> 3 <211> 123 <212> DNA <213> Homo sapiens <400> 3 gtttcattgg tcagtttaac agcaaatgcc ttgggttact cagaacttgg agccatcaaa 60 tctctcagga cactaagagc tctgagacct ctaagagcct tatctcgatt tgaagggatg 120 agg 123 <210> 4 <211> 6965 <212> DNA <213> Homo sapiens <400> 4 gtaagaaaaa tgaaagaacc tgaagtattg tatatagcca aaattaaact aaattaaatt 60 tagaaaaagg aaaatctatg catgcaaaag gaatggcaaa ttcttgcaaa attgctactt 120 tattgtttta tctgttgcat atttacttct aggtgatatg caagagaaat aggcctctct 180 tgaaatgata taatatcatt tatctgctgt gcttatttaa atgactttat ttcctaatcc 240 atcttgggag tttccttaca aatctatata caaaaaaaag ctgatgcatt attaaagtac 300 tatgtgtaat gatataatgg taatctaaag taaattctat atcaggtact tattctttgt 360 gatgatatac tgtacttaac gagttttcct gaaaataatg tgaatcacac atgtgcctaa 420 gtatgagtgt taagaaaaaa atgaaaggag ttgttaaaac ttttgtctgt ataatgccaa 480 agtttgcatt atttgaatat attcaagatt agatggttag atattaagtg ttgactgaat 540 ttataaaact agtaatacta acttaaagat tacatacaaa tccacatcat ttttataaca 600 ataaagtaaa acacttataa tgaacagaaa atataatttt gactcattac tataggtaat 660 ttatacatta accttaactt gcatcttatt ggtcagagtc acacaaaatg ttattttatc 720 cttttcaaag atgcaataat cattttccat catgcataac agattagaaa ttttgccatt 780 attgacttat tttccatgcc tttttttacg gcatgaagca ttagtttata gatatataat 840 ataaaaaatt agttctgctt ttttttaaaa aaaaatatta tcaaaacaaa acactgaatt 900 gtgtgattcc aatagaaaaa cactgctctt tcacctccta aggtgtagtt acttttatgg 960 aaactaagct gtattgtaga cttccatttg cactttgtag attgtttata gccttatgtt 1020 ctcttctcaa gtcttattat aaatgtcact ttgtaagaac gtaggacttg tcttcgattt 1080 ccctaacata tatgaaaact ttgtcctcat tatcgacaac tcagaacaat ataatacaag 1140 tagtcctctt ttatttctca cagagagcct caaattttca ccaaaatgtt aacagaaatt 1200 atctctgggg tgtataagaa ttaagtctgt tttccaatta aatgtcactt tgttttgttt 1260 cagactggca gtttcagttc tggagaaaaa aaatgtcatt tgtgtacatt ctacttgaaa 1320 acatgttgcc tgaatcaaaa taatatattt tatatggctt gtgaaatctg aacaatgcta 1380 aacatttgaa aatattataa accttttaca tttgaccatt tgaaagttta ttaaattcat 1440 tggtcaagtg ctcagatatt tccatacatt acacttcatt tctataaaaa agctgatctt 1500 atcggtatac ttttaatttt ctcagaaata accatatcta taattattaa tcaataatgc 1560 cttttatatt aaaagaggtt agtttttgaa acttggagtt ttagacataa aatccttata 1620 aatgctgata gtgatataac taatagttta aatggtcaga tttatgaata tggctctatt 1680 cctcataatg acaacataca cacagcacta aaatgactaa tctcttcaat acgtgtttgg 1740 cattgtagag tcaaaataac gttataattg attctatttt ttatacttct agtgtttgga 1800 tattttattt tgtaaaaata taatcatgaa tgatggtgag gttggatata agaatgatga 1860 ttatgattgg gaagtgagat ttgaacatgc tcagaaactc tcatttaatt ctttgcccta 1920 gcagcataaa atcacaatag ctgcgtcaaa gcgtaactca ggcactcatt ttatttttgt 1980 tgttctgtta ttttttcaaa gcatgtgctt ttatgcaaca ttactgaata aagcatgttg 2040 tacagtgctt gataagaagt tagaaagtaa caaataaatt atcatcacgt tgcactttgt 2100 gttttgcatg ttttatgcac atttctggct gacagctttt aaacatttat tgtatttcaa 2160 atttccagtc caaatttttc aacttgtaaa attaaactga gtgaattgat gtcgtgaata 2220 tctagggtaa aataaaattt gtgtttaaat ttgtattttt aatttcctaa cctaggaaat 2280 cttaaatacc ttctttttca aaagaactca agtcttaatg gatagggaaa cagacggaga 2340 gcatcatgaa caaaaagtaa caccaaatgt tctgtcatat cagatttcta actaataaca 2400 aactatatat ttctattttg tataggataa tcttgctcca acttggatgg ggtggagcgc 2460 tggttcctcc cctgagccct ttattatggg tactgtatta ccccttttgc tacctttaat 2520 ccttgcactg tgacttatgt gtagtggggt gagggaggga ttgggaaggg tactattatt 2580 gcaccacagt agggaaaata cattatttac atcctaatcc cctcttttca attgtcttaa 2640 atttcatttg aaaaaaaaaa aaacctttat gaatttaccc tctgtggatt ttaaccccaa 2700 tggttgatat ctttattaag tttcattgaa tatgatttag ttatgtgtat atggagttat 2760 ccatctttgg ggagattact ggattggtga gggcggggga ccctggtgta gaatgattat 2820 gtgaaaaaac aatttaactt gttaagctca tgatactgtt tgaggcatac agcccctgct 2880 gtttagtaca ttggtctggg tcctgaaaat taccagttag ataccatcag ttgattattg 2940 atatgtatga gcagatacta gggtgcaata tttcaggttt cataagactg gtattgattg 3000 tgaccactct cattttttat tgtgtaagtt catatggggt tattttcaaa atgttaacaa 3060 ggcaaaaata tattaagaaa tagttgaata agcacatgtg aattgtgttg taaacaaaaa 3120 gttagaataa aaaaatccac ttatttgaat tatgcagaat agaatacata cctagaaata 3180 aaacaaaaac gtcttatcat gagtattaag ataaaattta aggcataaac tcacttctta 3240 gaataagtaa ctcccaacta actttctagg attttaaaac ataacacagt gaaaacatac 3300 ataaacataa ctctacattt tatttattct taaagtttaa gtgtattata caagaagaag 3360 agtttatatt cgagagacag aaaaagtcag aatttttgtt tggatcacca atatatcata 3420 gcttacaaaa aaactgtctt aattaaaacc cacaacataa tttttttaga tttttaagaa 3480 agattctatt attcttcttt atacttaaaa atggatgatt cctactttgc ccacttttat 3540 ttttattcac atagattttc tttatttcta ttagagaagc actagaattc atgaatagtg 3600 ttgatttgaa gttcaaagta attaattcag ataaaaagac atttctgcat gtatgaaaat 3660 ttctaatgtg aatttgcata tttaattatc aatccttcat ttagtgtaga cttattttta 3720 aaaatgcagg taatgaacca gaaatagaat tggttgtgct agagtagaga aactttattt 3780 gatgattgtt ttgaaaaaaa agcttctgag aagaaacaac ctctagtaca gtattaattc 3840 attaagatag ctcctttctc agacatttcc tttcatgtag cctgaaagtt caatttgaaa 3900 tttgttcttt ccaatttatt cagactaatt ctgcctactt tcttcccccc ataagaacca 3960 attactgcag ctttattgag actgaaaaaa gttaatacac ctccttcttt gctgaaccaa 4020 ggaatggctt ggaactcttg ggaaaagaca atcttttcta tgatctttca ttgtctaatt 4080 taatacatca taaatatgac tatagctttg tataataaac tccccaatac tgtgccagat 4140 gttttctaag ataaagttat tttatgttca caaaaaaaat aaaacttttc tctgggccaa 4200 atgtatgcca actttgcaaa tcatatcctg aagtgcactg ctgcagagta catgcttgcg 4260 tcataaattc catagagttc gctttaactc taaatcaatc cccagtttca aagtaaacct 4320 ctcaaacata ttacctaagc acaaacttct ccctgtgctc agttccttaa ttattctcat 4380 cccatattca gaaataacat ttaaaaatta tgctttgatc aataaatact aatctaaact 4440 ttgcttcatt aacccattca tttttgtcaa ccattatttt attcctatat tcaaagctct 4500 ctggtatgtt cttatattca agacactcaa ggccctggaa gattcacgaa catatgtttg 4560 catcttaaat ttttagaaaa tcttacaatc tgtcaggatt acactgaact ctagtacaga 4620 gtaatatggg taccagataa gtgggagcaa ctcttccacg tagactggaa acagcactaa 4680 atgctattta taggctactt tctgaactta acttgtttta acctcatttt tctcatatgc 4740 caaatgagaa cgcaatactg aattatctgt acagttctgt tcagtactag aattctgatt 4800 cttgaattca aaggggaaaa cattcctctt tattttggag gctaaactgg gggacaaagt 4860 taggctccat gaaagaagtg ctatttgaac taaagccttt aagaggggag agtatttcag 4920 aagaggagct attagacaag gaatttcaat gtaaatggca tctcaatcac ctggcaatta 4980 tattagcaca cggttattat attaattgaa gtggcatgaa gtatagatga ccagggaagt 5040 taaaactgga aatatagatt gtggagtgat gtgaatacca aggtaagaaa aatatttgtt 5100 agttaccaga gagccaataa ataactttca agtgggactt ggggaagatt aattcatctt 5160 acatagatta aatgaaggag aaggttagga gacagatgac agtgcaagta tgaaataaca 5220 gagggcagtt ctaggtggtg actgtgagaa tggaaaagag gtggcaaagc tgagaaacgt 5280 ttcaaagaaa aaatgtgaga caggtaatgt gaaaagaaaa tcgagaaata ggtatagata 5340 atcagtgttc tgctcatact ctaaattggg tgttgaaggc aaaatacgta ttttaattag 5400 tactctgtgt atacacacta gaaacagcat tgtaatctgg atagtggaca aaatattcag 5460 aaaagaaggg aaatagtaac ttgatttcaa tttccaaatc tctaatctga aagaaatcta 5520 attctattca tccatttaaa ataaattata taacgagaat ttatgaagtc cattgtatta 5580 atgcagacag tcagatgaga taaggcaaag tgtcacgtgt cagcttggta gttgcatcgg 5640 ccacatcatt tggttctgcc tggataactc aaccaaatta atttttcata ctcatcccct 5700 ccacctttgt cattactggt attcttattt tctttggccc acttatcaca ctgttttatg 5760 ttccccagaa ggcctagagt tctttacagg ctttaaacag ggatcagaag tataagaaat 5820 tggctcatgt attttttttt cagacaggca gttaaaaaaa attgttctaa aaatacactg 5880 gcatcaaatg gcaaatagaa gatgttttga cgactacttc cattggatca gactgacaag 5940 aataatacaa gcacataggt ggaattaaac ttagctatta atgtccaagt ttgaggcagc 6000 tgccccttat aagcatttta gggtctgttt ttagcttccc tcttagccac tcctgtgcag 6060 ctccagtggg aggtatggag gaaaaagcaa ggaagccatc cctatgttgt ttccaaacat 6120 gaacactcaa gatttttaac tagtggtcca gaagtaaaga gggggaaaac atccttctat 6180 agaaaaaaaa aaaagtagat aataattgaa cacagaactt catgtgatca catcagattt 6240 gagaactatg tatggcatcc ctctttttct tattttccta agaaatgatt tctattatgt 6300 ttcatttgaa ataagttttt tgaattaaac tcagtaaatg aaacaactga catgactgga 6360 gcttgaaata aacgatgtga tgatctaatg aaatacataa tgcaaattgt cttgcttctt 6420 atgcaaaaat tattagtcat agcaatgcat gaataattaa agacaattat attaggtatt 6480 taataatatt ttttatattt atcatctgaa tttttaagtt attttaaaaa tatattggtc 6540 aaatcaactc aggtccaaat gttttagttt tgttctttaa tatattgcct ttttaaaatg 6600 agttaaactt ctgtataggc tttttaactt ttctttattc tgataacaca attctgactt 6660 catctggcag caagttcctc tgattttcct tttcctttaa ccttttaatg cttctccctc 6720 cctttttttt aaaaacattt ttgtttcatt tcttggttat attgcctata gttgttttcc 6780 taagtgtatt gcttaagaaa aaaaaatgaa ttttaagatt tttttgaacc ttgcttttac 6840 atatcctaga ataaatagca ttgatagaaa aaaagaatgg aaagaccaga gattactagg 6900 ggaatttttt ttctttatta acagataaga attctgactt ttcttttttt ccatttgtgt 6960 attag 6965 <210> 5 <211> 282 <212> DNA <213> Homo sapiens <400> 5 gtggttgtga atgccctttt aggagcaatt ccatccatca tgaatgtgct tctggtttgt 60 cttatattct ggctaatttt cagcatcatg ggcgtaaatt tgtttgctgg caaattctac 120 cactgtatta acaccacaac tggtgacagg tttgacatcg aagacgtgaa taatcatact 180 gattgcctaa aactaataga aagaaatgag actgctcgat ggaaaaatgt gaaagtaaac 240 tttgataatg taggatttgg gtatctctct ttgcttcaag tt 282 <210> 6 <211> 64 <212> DNA <213> Homo sapiens <400> 6 gataatcttg ctccaacttg gatggggtgg agcgctggtt cctcccctga gccctttatt 60 atgg 64 <210> 7 <211> 123 <212> RNA <213> Homo sapiens <400> 7 guuucauugg ucaguuuaac agcaaaugcc uuggguuacu cagaacuugg agccaucaaa 60 ucucucagga cacuaagagc ucugagaccu cuaagagccu uaucucgauu ugaagggaug 120 agg 123 <210> 8 <211> 6965 <212> RNA <213> Homo sapiens <400> 8 guaagaaaaa ugaaagaacc ugaaguauug uauauagcca aaauuaaacu aaauuaaauu 60 uagaaaaagg aaaaucuaug caugcaaaag gaauggcaaa uucuugcaaa auugcuacuu 120 uauuguuuua ucuguugcau auuuacuucu aggugauaug caagagaaau aggccucucu 180 ugaaaugaua uaauaucauu uaucugcugu gcuuauuuaa augacuuuau uuccuaaucc 240 aucuugggag uuuccuuaca aaucuauaua caaaaaaaag cugaugcauu auuaaaguac 300 uauguguaau gauauaaugg uaaucuaaag uaaauucuau aucagguacu uauucuuugu 360 gaugauauac uguacuuaac gaguuuuccu gaaaauaaug ugaaucacac augugccuaa 420 guaugagugu uaagaaaaaa augaaaggag uuguuaaaac uuuugucugu auaaugccaa 480 aguuugcauu auuugaauau auucaagauu agaugguuag auauuaagug uugacugaau 540 uuauaaaacu aguaauacua acuuaaagau uacauacaaa uccacaucau uuuuauaaca 600 auaaaguaaa acacuuauaa ugaacagaaa auauaauuuu gacucauuac uauagguaau 660 uuauacauua accuuaacuu gcaucuuauu ggucagaguc acacaaaaug uuauuuuauc 720 cuuuucaaag augcaauaau cauuuuccau caugcauaac agauuagaaa uuuugccauu 780 auugacuuau uuuccaugcc uuuuuuuacg gcaugaagca uuaguuuaua gauauauaau 840 auaaaaaauu aguucugcuu uuuuuuaaaa aaaaauauua ucaaaacaaa acacugaauu 900 gugugauucc aauagaaaaa cacugcucuu ucaccuccua agguguaguu acuuuuaugg 960 aaacuaagcu guauuguaga cuuccauuug cacuuuguag auuguuuaua gccuuauguu 1020 cucuucucaa gucuuauuau aaaugucacu uuguaagaac guaggacuug ucuucgauuu 1080 cccuaacaua uaugaaaacu uuguccucau uaucgacaac ucagaacaau auaauacaag 1140 uaguccucuu uuauuucuca cagagagccu caaauuuuca ccaaaauguu aacagaaauu 1200 aucucugggg uguauaagaa uuaagucugu uuuccaauua aaugucacuu uguuuuguuu 1260 cagacuggca guuucaguuc uggagaaaaa aaaugucauu uguguacauu cuacuugaaa 1320 acauguugcc ugaaucaaaa uaauauauuu uauauggcuu gugaaaucug aacaaugcua 1380 aacauuugaa aauauuauaa accuuuuaca uuugaccauu ugaaaguuua uuaaauucau 1440 uggucaagug cucagauauu uccauacauu acacuucauu ucuauaaaaa agcugaucuu 1500 aucgguauac uuuuaauuuu cucagaaaua accauaucua uaauuauuaa ucaauaaugc 1560 cuuuuauauu aaaagagguu aguuuuugaa acuuggaguu uuagacauaa aauccuuaua 1620 aaugcugaua gugauauaac uaauaguuua aauggucaga uuuaugaaua uggcucuauu 1680 ccucauaaug acaacauaca cacagcacua aaaugacuaa ucucuucaau acguguuugg 1740 cauuguagag ucaaaauaac guuauaauug auucuauuuu uuauacuucu aguguuugga 1800 uauuuuauuu uguaaaaaua uaaucaugaa ugauggugag guuggauaua agaaugauga 1860 uuaugauugg gaagugagau uugaacaugc ucagaaacuc ucauuuaauu cuuugcccua 1920 gcagcauaaa aucacaauag cugcgucaaa gcguaacuca ggcacucauu uuauuuuugu 1980 uguucuguua uuuuuucaaa gcaugugcuu uuaugcaaca uuacugaaua aagcauguug 2040 uacagugcuu gauaagaagu uagaaaguaa caaauaaauu aucaucacgu ugcacuuugu 2100 guuuugcaug uuuuaugcac auuucuggcu gacagcuuuu aaacauuuau uguauuucaa 2160 auuuccaguc caaauuuuuc aacuuguaaa auuaaacuga gugaauugau gucgugaaua 2220 ucuaggguaa aauaaaauuu guguuuaaau uuguauuuuu aauuuccuaa ccuaggaaau 2280 cuuaaauacc uucuuuuuca aaagaacuca agucuuaaug gauagggaaa cagacggaga 2340 gcaucaugaa caaaaaguaa caccaaaugu ucugucauau cagauuucua acuaauaaca 2400 aacuauauau uucuauuuug uauaggauaa ucuugcucca acuuggaugg gguggagcgc 2460 ugguuccucc ccugagcccu uuauuauggg uacuguauua ccccuuuugc uaccuuuaau 2520 ccuugcacug ugacuuaugu guaguggggu gagggaggga uugggaaggg uacuauuauu 2580 gcaccacagu agggaaaaua cauuauuuac auccuaaucc ccucuuuuca auugucuuaa 2640 auuucauuug aaaaaaaaaa aaaccuuuau gaauuuaccc ucuguggauu uuaaccccaa 2700 ugguugauau cuuuauuaag uuucauugaa uaugauuuag uuauguguau auggaguuau 2760 ccaucuuugg ggagauuacu ggauugguga gggcggggga cccuggugua gaaugauuau 2820 gugaaaaaac aauuuaacuu guuaagcuca ugauacuguu ugaggcauac agccccugcu 2880 guuuaguaca uuggucuggg uccugaaaau uaccaguuag auaccaucag uugauuauug 2940 auauguauga gcagauacua gggugcaaua uuucagguuu cauaagacug guauugauug 3000 ugaccacucu cauuuuuuau uguguaaguu cauauggggu uauuuucaaa auguuaacaa 3060 ggcaaaaaua uauuaagaaa uaguugaaua agcacaugug aauuguguug uaaacaaaaa 3120 guuagaauaa aaaaauccac uuauuugaau uaugcagaau agaauacaua ccuagaaaua 3180 aaacaaaaac gucuuaucau gaguauuaag auaaaauuua aggcauaaac ucacuucuua 3240 gaauaaguaa cucccaacua acuuucuagg auuuuaaaac auaacacagu gaaaacauac 3300 auaaacauaa cucuacauuu uauuuauucu uaaaguuuaa guguauuaua caagaagaag 3360 aguuuauauu cgagagacag aaaaagucag aauuuuuguu uggaucacca auauaucaua 3420 gcuuacaaaa aaacugucuu aauuaaaacc cacaacauaa uuuuuuuaga uuuuuaagaa 3480 agauucuauu auucuucuuu auacuuaaaa auggaugauu ccuacuuugc ccacuuuuau 3540 uuuuauucac auagauuuuc uuuauuucua uuagagaagc acuagaauuc augaauagug 3600 uugauuugaa guucaaagua auuaauucag auaaaaagac auuucugcau guaugaaaau 3660 uucuaaugug aauuugcaua uuuaauuauc aauccuucau uuaguguaga cuuauuuuua 3720 aaaaugcagg uaaugaacca gaaauagaau ugguugugcu agaguagaga aacuuuauuu 3780 gaugauuguu uugaaaaaaa agcuucugag aagaaacaac cucuaguaca guauuaauuc 3840 auuaagauag cuccuuucuc agacauuucc uuucauguag ccugaaaguu caauuugaaa 3900 uuuguucuuu ccaauuuauu cagacuaauu cugccuacuu ucuucccccc auaagaacca 3960 auuacugcag cuuuauugag acugaaaaaa guuaauacac cuccuucuuu gcugaaccaa 4020 ggaauggcuu ggaacucuug ggaaaagaca aucuuuucua ugaucuuuca uugucuaauu 4080 uaauacauca uaaauaugac uauagcuuug uauaauaaac uccccaauac ugugccagau 4140 guuuucuaag auaaaguuau uuuauguuca caaaaaaaau aaaacuuuuc ucugggccaa 4200 auguaugcca acuuugcaaa ucauauccug aagugcacug cugcagagua caugcuugcg 4260 ucauaaauuc cauagaguuc gcuuuaacuc uaaaucaauc cccaguuuca aaguaaaccu 4320 cucaaacaua uuaccuaagc acaaacuucu cccugugcuc aguuccuuaa uuauucucau 4380 cccauauuca gaaauaacau uuaaaaauua ugcuuugauc aauaaauacu aaucuaaacu 4440 uugcuucauu aacccauuca uuuuugucaa ccauuauuuu auuccuauau ucaaagcucu 4500 cugguauguu cuuauauuca agacacucaa ggcccuggaa gauucacgaa cauauguuug 4560 caucuuaaau uuuuagaaaa ucuuacaauc ugucaggauu acacugaacu cuaguacaga 4620 guaauauggg uaccagauaa gugggagcaa cucuuccacg uagacuggaa acagcacuaa 4680 augcuauuua uaggcuacuu ucugaacuua acuuguuuua accucauuuu ucucauaugc 4740 caaaugagaa cgcaauacug aauuaucugu acaguucugu ucaguacuag aauucugauu 4800 cuugaauuca aaggggaaaa cauuccucuu uauuuuggag gcuaaacugg gggacaaagu 4860 uaggcuccau gaaagaagug cuauuugaac uaaagccuuu aagaggggag aguauuucag 4920 aagaggagcu auuagacaag gaauuucaau guaaauggca ucucaaucac cuggcaauua 4980 uauuagcaca cgguuauuau auuaauugaa guggcaugaa guauagauga ccagggaagu 5040 uaaaacugga aauauagauu guggagugau gugaauacca agguaagaaa aauauuuguu 5100 aguuaccaga gagccaauaa auaacuuuca agugggacuu ggggaagauu aauucaucuu 5160 acauagauua aaugaaggag aagguuagga gacagaugac agugcaagua ugaaauaaca 5220 gagggcaguu cuagguggug acugugagaa uggaaaagag guggcaaagc ugagaaacgu 5280 uucaaagaaa aaaugugaga cagguaaugu gaaaagaaaa ucgagaaaua gguauagaua 5340 aucaguguuc ugcucauacu cuaaauuggg uguugaaggc aaaauacgua uuuuaauuag 5400 uacucugugu auacacacua gaaacagcau uguaaucugg auaguggaca aaauauucag 5460 aaaagaaggg aaauaguaac uugauuucaa uuuccaaauc ucuaaucuga aagaaaucua 5520 auucuauuca uccauuuaaa auaaauuaua uaacgagaau uuaugaaguc cauuguauua 5580 augcagacag ucagaugaga uaaggcaaag ugucacgugu cagcuuggua guugcaucgg 5640 ccacaucauu ugguucugcc uggauaacuc aaccaaauua auuuuucaua cucauccccu 5700 ccaccuuugu cauuacuggu auucuuauuu ucuuuggccc acuuaucaca cuguuuuaug 5760 uuccccagaa ggccuagagu ucuuuacagg cuuuaaacag ggaucagaag uauaagaaau 5820 uggcucaugu auuuuuuuuu cagacaggca guuaaaaaaa auuguucuaa aaauacacug 5880 gcaucaaaug gcaaauagaa gauguuuuga cgacuacuuc cauuggauca gacugacaag 5940 aauaauacaa gcacauaggu ggaauuaaac uuagcuauua auguccaagu uugaggcagc 6000 ugccccuuau aagcauuuua gggucuguuu uuagcuuccc ucuuagccac uccugugcag 6060 cuccaguggg agguauggag gaaaaagcaa ggaagccauc ccuauguugu uuccaaacau 6120 gaacacucaa gauuuuuaac uaguggucca gaaguaaaga gggggaaaac auccuucuau 6180 agaaaaaaaa aaaaguagau aauaauugaa cacagaacuu caugugauca caucagauuu 6240 gagaacuaug uauggcaucc cucuuuuucu uauuuuccua agaaaugauu ucuauuaugu 6300 uucauuugaa auaaguuuuu ugaauuaaac ucaguaaaug aaacaacuga caugacugga 6360 gcuugaaaua aacgauguga ugaucuaaug aaauacauaa ugcaaauugu cuugcuucuu 6420 augcaaaaau uauuagucau agcaaugcau gaauaauuaa agacaauuau auuagguauu 6480 uaauaauauu uuuuauauuu aucaucugaa uuuuuaaguu auuuuaaaaa uauauugguc 6540 aaaucaacuc agguccaaau guuuuaguuu uguucuuuaa uauauugccu uuuuaaaaug 6600 aguuaaacuu cuguauaggc uuuuuaacuu uucuuuauuc ugauaacaca auucugacuu 6660 caucuggcag caaguuccuc ugauuuuccu uuuccuuuaa ccuuuuaaug cuucucccuc 6720 ccuuuuuuuu aaaaacauuu uuguuucauu ucuugguuau auugccuaua guuguuuucc 6780 uaaguguauu gcuuaagaaa aaaaaaugaa uuuuaagauu uuuuugaacc uugcuuuuac 6840 auauccuaga auaaauagca uugauagaaa aaaagaaugg aaagaccaga gauuacuagg 6900 ggaauuuuuu uucuuuauua acagauaaga auucugacuu uucuuuuuuu ccauuugugu 6960 auuag 6965 <210> 9 <211> 282 <212> RNA <213> Homo sapiens <400> 9 gugguuguga augcccuuuu aggagcaauu ccauccauca ugaaugugcu ucugguuugu 60 cuuauauucu ggcuaauuuu cagcaucaug ggcguaaauu uguuugcugg caaauucuac 120 cacuguauua acaccacaac uggugacagg uuugacaucg aagacgugaa uaaucauacu 180 gauugccuaa aacuaauaga aagaaaugag acugcucgau ggaaaaaugu gaaaguaaac 240 uuugauaaug uaggauuugg guaucucucu uugcuucaag uu 282 <210> 10 <211> 64 <212> RNA <213> Homo sapiens <400> 10 gauaaucuug cuccaacuug gauggggugg agcgcugguu ccuccccuga gcccuuuauu 60 augg 64 <210> 11 <211> 170057 <212> DNA <213> Mus musculus <400> 11 taaaataaaa aattaatttt attagatttg cacatttttt aattgtgatt agcatcattt 60 tgggctaata gtagcatttt ccaacatgca gttcatgaat acggtttgcc taaatatttt 120 ttttttaaga aaaagaggtg cctacggtct gcttctgtaa gaaacacaaa tatcttgatg 180 taattgacta tataagtgta atcctctctg attttgagga aaagaaattc tgaagcccac 240 atttatattt agaacaatct aaagaagcat gatttcaaag caaagaaaaa taaacagaaa 300 ttggggaaat aaagaaaaaa atgagaaaaa aaagcactct ggtcatctgt tagcacaaac 360 actacaataa atataaatca aatgttatac cttttccaat tgcaaatcat aatttggatg 420 tgaagttgtg agtgtatttt gccccttaaa attatgaaat aatccaaaat taacaattgt 480 aataaaaaag cagagatcta ccactaccca gtcatagttt catttcttag ttagcaaata 540 tcttccatga aaaactgctg tggacagaaa gtaagaaaag tgattgtgat atcaacctga 600 agataatttc ctcttcatat gtacataatg ctgaaaagta aaagaaagtg actttgtaca 660 gtatttatat ttgcttataa aactctaaac atgtttttaa caggttaagc agtagtgttg 720 tcttttgaac acgtatgtac agtctggcta tacattgaac gttatccact taaattttaa 780 aaacaaccca aacattgtta aagtgctgca aactattgct taatgactta aagaaatgaa 840 gtctgctgaa cagtttcctt gacttagcca ctgacctatg gtttctcgtg agtgagattc 900 tgagtgctga gagaaactag ataccgcaac gtggtaatat cgacatgcat tggcagcatc 960 cacactatct acaatggtac agagtacagt atatttccgg tggacagctt gcactctaca 1020 tttctcgtgg tacatatttg atgcaataaa tactgtgctt acgtcattat ttgtttgctc 1080 aaacgtgcac cacagagtaa aatgactatt tacataataa atagcatttc attaacacat 1140 acagtgtcaa ccttgctgag agctgaagat ggctaaacaa agtgcaggag gaagcgggga 1200 tttataaagg gttcttttgg tcaattcgct ctgctagggt tgggggtagg gagtcagagt 1260 cataatttag agacctttca gagacagtga acagaaatgt agcgtgactc cagacatttg 1320 aatgaagttt gcacctccta agacttgatg acctgtctga acaatctcct tggactaagg 1380 actagatttt gacaaaccca gctcagcaaa gcccacgatc tagcgatcac ctccgtaccg 1440 ccccctcccc ccgcagaaac acagatgaca tagaactgtt gaagaactgt ctttgctttc 1500 ctttcgactt tttctcatgc atgatcctaa ggtgcaacat gccctcatgc gaaaccacac 1560 cgttgtgcag acgggagggc cataaggatg tcaacactcc caggtgacac accgggaaaa 1620 gagttccttt agtctatttc ccaacagaaa ccctgcttac aaaaatagtc acatgtaaca 1680 aacaacacat ggattaaaaa aaagatgaat ccactaacag agtttgtaaa aaacctgaca 1740 aatgtggcag ttgaaatgca aacggtggat agagttacta cactaaagtg tttcacatta 1800 acccccaaat tatagctctg caccccttta gactgatccc tacagtctgc atagccattt 1860 gtctcttgtc ttcagcagtg tcagctggta gttagaacag taccctcctg tcaaggttat 1920 ctccccttta cacagtcaca gagtttgccg acaagggggt cactgtctta ttgaggcact 1980 gaccttaaag tgaatttgtg taaaaacagt cagtttggca ttgacttctt aaaggagtcc 2040 ttttgacttc acaggctgta aacaatttgt cacccaattt attatttttt tttgttgttt 2100 ttgttcattt ccctttggct ttttcatcct tcccttcctg ctcgtgtttc tccacgattg 2160 gctttgtcac ccgatcgtag gagggcggac aagctgctgt ggacattgtc aggtcagttt 2220 tctccgtaat agagttttcg tttattctgt caatgagcat gtcttctttt acaagaagat 2280 tagccccacc tttgagtttg ttcttattgt atgtgaatga agcttgtttt actgttcgct 2340 tcaaaaggtg gcgcctataa gctcgctgaa tgataacagc tgacacctcc tcttgtttgc 2400 gttttaatgt agtagtgatg ggctgataag agaccttgga ggggttggaa gccatgaacc 2460 gctcttccat ctggattcga agagcatcca tctctccact ctcacccaac acccgctttg 2520 taaaagcaaa taagatgtcc aggcagtgga tgcggtctcc actcaccatg ggcaggtcca 2580 tggcaatgag ctgaagtttg tttggttgtg gcaaattgag agggggttct agagcagctg 2640 caaactgaga taatttttca aattccatga actgggtggc gtcagggtcg aacttctccc 2700 agacctcgta gaacatctca aagtcgtcct cactcagagg ctctgcactt tcttctgtgg 2760 caacgctgaa gttctccagg atgacagcaa tgtacatgtt caccacaacc aggaaggata 2820 tgatgatgta gctgacaaaa aagaaaatcc ccacagatgg gttcccacag tctcccttca 2880 ccgagcttcc agggttaact ttattagggt cacagtcagg gggtttgctg ttgaggatgg 2940 gggccagcag tccatcccag cccgcagagg tggtgatttg gaacaggcag atcatgctgt 3000 tgccgaaggt ctcaaagttg aacatgtcat caatcccaac ttccctctta acataggcaa 3060 agttggacat cccaaagatg gcgtagatga acatgacgag aaaaagcagg aggccgatgt 3120 taaacagcgc aggaagggac atcatcagag caaagagcag cgtgcggatc cccttggcac 3180 ctttgatcag gcgtaggatt cgtccaatcc tggccaggcg gatgactcgg aacagggtag 3240 gagacacaaa atacttttct attagctccg caagaaacat ccctgtggga agataattaa 3300 actatcaatc agtgaagaag tcatcaacta atcatttatt aaaatatttg agttattaaa 3360 gttccaatgt caatttcaga gtattaagat tcaattttgt aatcttgggt atggtacaaa 3420 tatattccaa tcattttcca gtatctgcag ctgatttgtc ccaggatgca cctctcctcc 3480 ttagaacatc aaaattcaag gactgaaagc cctttatatc atatggcagc acatttgcat 3540 acaatttgtc tataccattt tattgaaagt tttgaattat atttaaaatg ttcatcacat 3600 ttaacaatga aagtaccatg tgaagagttg ctgtgatatt ccagaaatcc aatcctaact 3660 aaacaacaac aacaacaaca acaacaaaaa ccaagtaagg ctgagtggag gtggatccca 3720 gtactcaaag gcagagggag gggatctctg ttagtgtgat ggtagcctgg tctacagaac 3780 gagtttcagg acagccaagg ctacatagag gaaccctgac ttgaaaaacc aaaccaaatt 3840 aaaaccaacc aaccaaccaa ccaaccaacc aaccaaccaa ccaacaagaa aacaaacaaa 3900 caaacaaaca aacaaaaaca aaaaatccaa aacagaacag ttgctaccgt tcattatatt 3960 aaaaatggtc aggagaggag catggttctt aaaaatactt ttgatctgtg tttgaatttt 4020 cagatattta atacatacat atggaaaact gagtgtttat agaattatac gatgtataat 4080 aaaagttaac tttagctttt actcagcctc agcaatagat taaaatttaa gaatcatagt 4140 acagctcgcc cccccaagag catttattta tttatttatt tatttattta tttatttatt 4200 tatttttggt ttttcgagac agggtttttc tgtgtagctc tagctgtcct ggaactcagt 4260 ctagaccagg ctggcctaga actcagaaat ctgcctgcct ctgcctccca agtgctggga 4320 ttaaaggcat gtaccaccac gcctggcccg aagagtattg atatgctatg gttaacttaa 4380 aatctcatca gaaataaata cgaaaatttg cttcaatgtc aacagccaac aatatatgaa 4440 tatgatgttt tttctctaaa cttgttgaac caaacttttc tttttcacac ttcactaatc 4500 tgaagtcttg gagtgtttca tgctgttttc atcctcatat gaactaatat tattacagaa 4560 ttgtccgtgc atgtgcctgt gtgtttgcaa aacactccag ggttgatgtt cttttcctct 4620 cctgtagcaa aatctcaatt ttttaatttt tacagctttt tttctccctg tgattttggg 4680 ttttttggca catgtatgtt catgtggcat gtgctctctc tctctctctc tctctctctc 4740 tctctctctc tctctctcgt gagtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 4800 gtgtgtgtgt cttacctgag gctgatgctg ggagtctctt tgattgcttt ctactttatg 4860 tatttatttt caatttttaa aatttttatt ggttatttta tttatttaca tttcaaatgt 4920 tatccccctt ctcattttcc cctcccaaac cccctgcctc tataagggtg ttcccccacc 4980 atcccatcaa ctcccacctc agggccctag catttctttt gcggggtcat cgagccatca 5040 caggaccaag ggcctccctt tccattgatg aatgacaagg ccatcctctg ctacatatgt 5100 ggctggagcc atgctccatg tgtactcttt ggttggtggt ttaggccctg ggagctctgg 5160 gagctttggg agctctggtt ggttgatatt gttgttcctc ctgtggggtt gcaaacccct 5220 tcagctcctt cagtccttgc cctaactcct ccattgcagt ctctgtgctc aggacttctc 5280 aattgaacac agagctctct ggtagcttgc cagataattt gaggggttcc aagagccttc 5340 tttataaggt gtcacccttg gccaggattt acactggtgc tgggaatctg ttctctcgtt 5400 ctcaagcttg cacactaagt gctttagatg ccactgcatt tctcagctcc cccctctgtc 5460 ctttaaataa agactccatt aaagagtact tccaacacaa acacacacac acaccaccac 5520 caccaccacc accactacca tcaccaccac tatcaccacc accaccatca tcaccaccac 5580 caccatcacc accaccactg ccaacagcaa taacaacaac aaaaacctac ctattcaacc 5640 aaccaaaata cccaaatgca tcattgtatg caaagcacaa aagcatcatt ctctttagtc 5700 agccttctct atctcagtct ctatctctgt ctctttcggc ctctctcttt ttgatgctat 5760 ttacatgatt attgttggaa ttaaaaatta catataacat atgggttgga ttttagatgt 5820 aaggcctatt tattcagagg ggggaatagc acacagatca ttccaactga gtcctatgct 5880 tgaaaatttg caatgatttc atcttaatta ggaatgaagt tcccatacag ggacttcttc 5940 acttctctga agcattgttg gtatctgcag tgagatgagt taccttcatg aggctcttat 6000 gtactacaca atttgtagga taggactaag aaagagatgt tccatgctac cagtttcctt 6060 ctggaaatat tgaaaatttc tgtatgaaag ccacaagaaa ctactgttag tctacttgca 6120 tttcccattt acttctatcc atgttctact ctgcatgctg gtgaccccat taactacatc 6180 tctaatgtaa tgtctttcct gaccttcaga ccagattctc agtacccctc ttaccagaat 6240 catctagatc agtggatcta aaccttccta atgctgcaac cctttaatac agtttctcat 6300 attgtggtga ccaccaatca taaagttatt ttgttgcttc ttaataattg taactttgct 6360 actgctatga atcttaatgc aaatacctat gatttctaat ggtcttaggt gacccctatg 6420 aaagggctat tcaatcccca aagtgttgcg acctacagat tgagaatcat tgatctggat 6480 agcgtataga gtgtttaatc tcaaccacct aaaagcactt tttaaatttt ggttcaccac 6540 atcaatctat ttaatatatc tcaataaagg agatcttatt aatggtcaaa taaatatgtg 6600 atgcaatggg ataaaatatt tgtataaatt agaagcctaa ttttggaaga aaaacaaata 6660 caactcaaaa acacatgcca acatattgac tttgagtagt gagatgcctt ccactctaaa 6720 ttcctgtttt caacctccac ttttatcagg aggaatttgc cagactttgc acagatctta 6780 cctacaatgg agaggatgac caccacaaaa tcgaaaatgt tccatccaat ggtgaaataa 6840 taatggcgga gcgagatgag cttgagcaca cactcgccgg tgaacaggac gatgaacacc 6900 aggttgatgc gtgacaaaat gcttgtcaca taatcgctct ggtcatccgt ttccaccatc 6960 atggtcacca tgttcagaca gatgaggatc atgatgctga tatcaaacac ttgtctggtt 7020 acaaagtcaa aaaccattcc ttgaaatttg ttctgcagag aaacaaagac actttcagca 7080 atgcgggaga ttcctggtag acagcatata cattaaatac ttcctatatt ccctactttc 7140 tagtattgta catagtacct acctattggg acaaatattt gtaattggtg ccttgtagaa 7200 catttttata tctagttaat taaatttttg ttttgaggca tgcatattcc tgaatacatc 7260 aatcccttgc tgtagattct ttccctgcac actctttaca gaaacacaca gtgaatttca 7320 acacatcaag gttacagaac tgtaagaaat ctgtttgatt tgctgttgcc aaactttggc 7380 tcactggctg tagtactttc caatgagcag ctagacaatg tggtcattta taaacgtaat 7440 aaatattagt cttaaatttg ctttgttcct agagaattat caaaggaacc ttgtgatttc 7500 aaggatgcat ctgaaacacc aaacatttac attcctgctg ggcaagtagc acttgggggg 7560 tagaggcagg tggatttctg agccagcctg gtctacaaag ggaattccag gtcagtcagg 7620 gctacacaga gagaccctgt ctcaaagagt aaaataaaat aaaataaaat aaatttacat 7680 ttcaccttga caacattaat ttgttcccag caagtggtct ttgctgatat tgtcagacaa 7740 ataatgatga gtctccacag gggtaatcag actgaaaaga cattgcttgc tatgctataa 7800 caaagggagc acatgtcctt cgctactcat gtgtagtcag ctgaggttag gcccagtaca 7860 ccatcttctg cttatttctt tgggccactg aagaatccta agcatatttt agtaccataa 7920 aatacccctg ctgtgcagta cttgacttgt gtagcactaa gtatcaatgg ggaaaatgtt 7980 ctcattagac actttgcctc ttcttagaac tgggaacaaa acacccatgg aaggagttac 8040 agagacaaag tttggagctg tgacgaaagg atggaccatc tagagactga catatctggg 8100 gatccatccc ataatcagct tccaaacact gacaccattg cacacactag caagattttg 8160 ctgaaaggac ccagatagag ctctctcttg tgagactatg ccggggccta gcaaacacag 8220 aagtggatgc tcacagtcag ctattggatg gatcacaggg cccccaatgg aggagctgga 8280 gaaattaccc aaggagctaa agggaactgc aaccctatag gtggaacaac attatgaact 8340 aaccagtacc ccggagctct tgtctctagc tgcatatgta tgaaaagatg gcctagtcgg 8400 ccatcactgg aaagagaggc ccattggaca ggcaaacttt atatgcccca gtacagggga 8460 atgccagggc caaaaagtgg gaatgggtgg gtaggggagt gggggggggt atgggggact 8520 tttggtatag cattggaaat gtaaatgagg aaaataccta ataaaaatat taaaaaaaga 8580 aagaaagaaa gtagtgcttg aactggacag tagtagagca tgcttttaat cccagcactg 8640 gggaagcaga ggcaggtgga tctgagttca agaccagcct gatctacagt gtgagttcca 8700 caacagccaa aactccaaag aaaaaccctg cctccaaaca aacaaacaaa caaacaaaca 8760 aacaaacaaa attggctagt acaatagaaa cattcactaa gattctgttt tgtaattcat 8820 catggggaat attttaagct taagatcact gccatagtca aggacaccac aagaagacct 8880 acagtgtcaa ctatcctggg accgtggaga ctcacaaagc ctgggccacc atccagggag 8940 cgtggtggag ctggatctag gtaccctaca catttgtagc aagtgtgcag cttgtcttca 9000 tgtgggttcc ctaacaagct gtctcagtct ctgcttcctg tcactggagc cccctcctct 9060 tacctagact gccaggttag tccttggtgg gagaggatgt gtctagttct gatgggacta 9120 gatgtcccat ggtggagtgg tataaaaggg ggatcccctt ctttgaggac aaggggaggg 9180 gacaatagga agaaggattt gttgtgatgg tgggactagg aagagaggag ggagggaggc 9240 tgtgattggg atataatgtg aataaaagaa ataagttatg gaaaaaaatc actgtcataa 9300 aaataaccat gataagggct ctttctcctt tatagtttgt agatgaatct tggaaatatg 9360 agaatggtta tttattatca caaattgtaa taatgccgac ataagcaatt gctgatttta 9420 gagccataca aaaacatatt cattactggg atgctcacct cctctaaaat ggtccatatt 9480 tctacttatt aaacaacaat tacaagtgga gatgatatgc cattgagcat cttttctacc 9540 tctttaatca gaaagtaaat gaatattagc cccaccctat gcttctgtat tgcttgacat 9600 tgcactgcag ctactgtaaa gtcataaaga cacaactatt gtgaggacca cattagtcta 9660 cgtagtttgg attctaagtg tgtagttgta ggtcatttgg agacaaattt gcattttctg 9720 tatattctta ttctttttgg tctttaaaaa aaatatcaaa acatagatta gagatactca 9780 aaaggttttt tttttccttt ttcttttttc ttttttcttt tttcttttgt gctgggaatg 9840 gtagttgatt tcccctgaga aacaaaactc atttcaggtt gttgctttat attattttca 9900 tttgatattt cttactccag gtcgagggat aggcttttgt ggcttttttg atcctaattt 9960 cttcattgca ttatagtatt tcttctgttc ttctgtcata aagatgtctt gacctccaaa 10020 gtatagaaaa aaaaatcaaa gctggttaaa attgtatcca ttccctcata acttttcaat 10080 attataacaa gagatttcaa gagattaaca tggttatcct tgtgacttat tttgaatttg 10140 aaaattaaaa gtacactgta ttgactataa tacttaagtt ttaagataac taaaattggc 10200 attattatta taattattga aggaaaaaag cccagacatg gtaaaacaca aagctccatc 10260 ttccttctgg cccacacttc cacctacagt cagggaccag caccctgagc tctccttcac 10320 aacctgtctg cctcatggga gttcttctcc caccagaaca accagctcca tgtttcagtc 10380 cacacctcta cctgcaattg gggatctata ccctacacct cagccaacag ctctgcttgc 10440 ctctggggag ggctttagct atctaggaca acaagtctct gagagttact actcccaagg 10500 acttacaggc cagccaacac cagagaaaaa aatagatggc gaaaggcaag ctcaatagaa 10560 caatagaata atcgctagaa gccagtgcag tatggcacct tcagaactga gctctcttac 10620 tacagcaagc cctggatatc ctaacacacc tgaagagcaa tacttgacct taaatcccat 10680 cttatgaaga caatagaggc cattaaagat gatataaata aagcatatgc agaatatagg 10740 aaaatacaac taaacaggta gaaatcttta atgaggaaac aaataaatcc cctaaagaaa 10800 tatgaaaaat acaatcaaac gggtgaaaga aatgaataaa atggactcag atttaaaaat 10860 agaattagaa gcattaaaga aaacacaaat ggaagcaacc ctggagatat aaaactgagg 10920 aaagagagca gggactacac acataagaat caccaacaaa atacaagaga tggaagaaag 10980 aatctcagac agaggaaatg caatagaaaa aaattaatac attgataaag gaaaatgcca 11040 aatgaaaaaa gttcccaact caaaacattc atgaagttgt gatacgatga aaagactaaa 11100 cctaagaata atagaaataa aagaaggtga agattcccag ttcaaagggc taaaaaatat 11160 cttaaacaaa actatagaag acaactttcc taacctaaag aaagggatca ctatagaagc 11220 ttacagaaca tcattagatt ggaccagaca agaaaatttt ccttccacat attaaaacac 11280 taaatatata gaataaaaga tagaatatta aaaactacaa gggaaaaggg ccaagtaaca 11340 tataaaagca tacctaatag aattatacct gacttcccaa cgaacctcta aaagtcagaa 11400 gatcttgcag atgctaagag actacagata gcagcccaga ctattatacc cagtaaaact 11460 ttcagtcatc atagatgaag aaaccaagat attctatgac aaacccaaat ttaaagagaa 11520 tctttctact aatacatcct ataatggata ctagaagaaa aactccaaca caagaagagt 11580 aactacaccc aagaaagcac aagaaattaa tcatcttaca gtaaaaccaa aagaagagaa 11640 tcacacacac acagaaccac cactaacatc aaaataagag gaactaacaa tcattggtca 11700 ttgataaatt tgagtatcag tagactcaat tcaccaataa aaagacaggc taacagacac 11760 gtaaacaatt tccatcattt tgtggcatac aagaaacaca cctcagcaac aaaaaaagac 11820 actacctcag aataaaggcc tcaaaaaaag ttttccaagc aaatgaaccc aagaaaccag 11880 ctggagtagc tattttaata gctaataaaa tagactttca accaaaattg gcaaaagaga 11940 tggggaagga cacttcatac tcatcaaagg gagaatccac taagatgaca tctcaattct 12000 gaacagctat gccccagaag caaggaaact cacatttgta aaaggaactt tactaaggct 12060 caaatcacac attgaaccct acacaataat agtaggaaat gtcaacatcc cactttcacc 12120 aatggacagg tcattgaaac agaaactaaa cagagaatca atgaaactaa cagaagttat 12180 gaaccaaatg aatttaacag atatctaaat aaccacccca aaaccaaaga atgtggcttc 12240 tactcagcac ttcatgagca ttttctaaag ctgaccatat aattgggcac aaagcaagcc 12300 tcaacagata caagaagatt catattaccc cttgcattgt atcaggtcac cagggattaa 12360 ggctagactt aaaaaaaaaa aagaacaaca acaacaacaa caacaacaac aacaacaaca 12420 aaaacccaga aataacagaa agcccataaa cttatggaaa ctgaataact ctatactcaa 12480 tgatcactaa cttggtcagg aagaaataga gacagatacc aggtgccaaa gttaaatcag 12540 gataagaata accatctaca cattcctata acccctaagg aaatagaagc aggcattaaa 12600 cttctcccaa ccaaaaaaag tacagggtca gatggtttta gtgcagaatt ctaccagaat 12660 accaatgctc ctcaaactat tccacaatat agaaacagag gaaacactac ctagttcact 12720 ctatgtggcc acagtcactc tgatacttga attacacaaa gactcaacaa agaaagaaaa 12780 ctacagaacc attttgtcaa tgaaaattga tacaaaaata atcaataaaa ttctcccaga 12840 cccaattcaa gaacacatca aaaacatcat caccatgatc atataggctt cataccagtg 12900 atgcagggat ggttcaatat gtaggaatcc atcagtgtaa tactagtact ccccaaattc 12960 ttccaaaaat agaaacagaa gaaacactac ctaattaatt ctatgaggcc acagtaaccc 13020 tgatacctaa accacagaaa gactcaacaa aggaagaaaa cttcagacca atttcactta 13080 tgaacatcta cgcaaaaaac actcataaaa tattcacaaa ccaaattgaa gaacacgtca 13140 aacacataat tcactacaac caagtaggcc tttcatcaca gggatacagg gatggttcaa 13200 tatatgaaag aaaatctatc aatgcaatcc actatacaaa caaactgaaa gaaaaaaatc 13260 acatgatcat cacattagat gctgagaaaa cctttgacaa atccaatact cctttatgtt 13320 aatcataata aataaaaaat gaatgcaacg aacaaatagt atgaaatcat gggacataaa 13380 gaaatataat tggctgggat gaacttggat acatccaaaa ctatttgcca taaaatgcac 13440 aaaaaataaa gttaaatttt gtttcccttt aagagatgtc aaatattaac aactaaaggg 13500 aatgtctggt gtctgtgaga gtggtggagc aaggtcatgc tcacatagct tattcagttg 13560 actagttatt taactacaag gaggcaatat acttcactct ggaatttaat gtaagaaaag 13620 atttaaacac tcaaatgttt tgcaggaaaa aattacttaa gtcactaaag attagataga 13680 ttgaaattgg ccaagttatg ataaataaac atgaacactt ttaacaaact gagaaatctc 13740 tgtgataaaa gtatttaaaa ttgtacattg ggaaacattt cagggctggg accatggctt 13800 agtgcatata ggcatttgct tacaatccaa atcacctgga ttcaatccct gggactcaaa 13860 gggtggaagg agggagacca tatcctgtaa gttgtctact gactaccaca cacccagtgt 13920 ggcatgaata aataactgta attttaaaaa gtatttcaga gatggctgaa gtgataaatt 13980 tattacacat tggcgtgaat ataagctcag atcccaaccc ccatgttaaa gtgggcatgg 14040 cactatgtta ttaaaacaaa aaccaaatgg tgatggggat gcagagataa gatgaatcca 14100 ttaatctcac tggccagcca tcaatctgaa ttgaagagga gattcaatga gaactcctgt 14160 cttaaaaatt atggtgggta gtgattgaga aaggtgacta atgtttatca ctggctttta 14220 catgcatgtg tacattcatc ctcacagaca cttgcacaca ccaccacgaa tacacataca 14280 acacaacaca atacaacaac acacacacaa cacacacaca cacacacaca cacacacaca 14340 cacacacaca cacacacaca cagagccaca tatgtacaca gaatatttca gggtcagaca 14400 acgtgatatg tgactatagt tccaatttat ttgagaagga tacagggctg ctacttgttt 14460 taggtcacat agggccatat agtgagatca ggtcagccta gattgaaaag tgagaccatc 14520 ttaaaagaaa aaaacagatg agaagtagtt caaaaaagga gactgttcat ggaaagagtt 14580 tgagcagaca aagatgaaat gtggaccatt gttactactg agtgataata tttgcatgct 14640 tcctttagtg cacatatata attgaaataa tcaaacatgc cttaagaatg ataatagata 14700 aaacaaaaat tcctcaaatt agaactagaa gtggttgcta ttaattaaat aaccagaaga 14760 aagaagtaca ggtagaaaag agtacaaaag aagtatatac actgaaccgt attttaaatg 14820 atggataatt actgactatg tataatcatg ggatttagtg tgatattgta gtacagacat 14880 gccagtgttc tctgatcaaa tctaacccct tttccctcac ctttccacat gcttttccag 14940 cctctagtga tcttttagct gcgaatacct tataaagggg agtgagtgag gagttattaa 15000 ggataaaaca tagggaaaag gtcgtgagct atttggtttc tgaattcaag atctcatctt 15060 gaattccaat tcaaatagaa tgttaattac tctgattcct tgtgttagga aaaattgtaa 15120 aaatacttat cttcttcttt tgctggttga aattgtcgat aatgacacca ataaacaggt 15180 tcagggtaaa gaaggacccg aagatgatga agatgacgaa gtacaaatac atgtacaggc 15240 tttcctcata cttaggctgt agttcaacct gccaacggag ggaatttgtt aactgataaa 15300 gcagtttgaa tactgggagc aagtcggtgc ttctacacaa gagtagaagg ctatatatat 15360 tcttagaaat aatttagtgt attttattcc catatcaaca gcctcaaaga aacaaaaaac 15420 caaaaaccat ccttgaaact aggaagcaaa aagtttttgt gtaaaaagtg atgcaattcg 15480 tcactctaac actaattgca taattttaca tagtataact gacattctgt tatttggata 15540 atagacttta gatttggtaa gttttaagtt aattgatttt cagtaatttg aaaatactag 15600 tgtggtgtct tatgtctgtg caactccaga atttgggaag ctgaggctgg agacttgttg 15660 agtactattc tagcctgggc cacaatgcaa catcctgtct ttaaaacaac caaagaaaaa 15720 gttagtgaaa aattagctct tataaatata gagaggacac ttttatagtc aagattcact 15780 tgtgtatgaa cttatatagc aaatgaagga actgaagtat tcatttggat gctggcatct 15840 tgccctacca gtaacaaagt cattaaaatt tttggattga atagacacgt tcaatgattt 15900 attttataaa atcctccatt gacgactgac tctcagactt gcagttataa aaatagacac 15960 agggctgtca ctcaatgcat aacaatggag tcaatattta gtataaatag gtaactactg 16020 cagtcttcta tttttaaaga caacagctaa aattaactga acatctaaga caaactctat 16080 gcaacaaggt gagatgatgc aattccagag gtgatcaaga agtttgtagg ggaacaggac 16140 gatttcaaat ttatcattgt ctccatagta agctagaggt ctgggttacc gaagaaaacc 16200 aaaacaagaa caagaataaa aaaacaaaaa caaaaaacaa aaaacaacca agtaacagga 16260 aagaagaaaa cagagatttt acagttttgg agatcaatct tagaggaagc ctgtgatttt 16320 tgagtacatc tgaaagctag gaaaagtatg gaatcaataa agtagaaatg ataacagtgt 16380 tggtacatag gaaagctagg aaaagtatgg aatcaataaa gtagaagtga taacagtgtt 16440 ggtacatctg aaagctaaga aaagtatgga attaaaaagt agaagtgata acagtgttgg 16500 tacacactcc agtgaatgca tgggtgctgt tcttataaag gatggattta gaaaagacta 16560 tgacacattt ctaagatgtt tagcctgcat ctttagcctt tcaggcttca aagcatggag 16620 cctgcctaca cagttcagct actgaagaca gtcatatatt cttctatgtc ctttatacaa 16680 caaatagaaa cactttggag aatatctgtt gcttattaaa tgaaagagtt gaattttttc 16740 tttcattttt tgacttccat ttttttttct gaactcagta caatatctct gatagacact 16800 gctgtgttaa gtacaaactc aatatactgt cttcctattt tttaattaac taaaatggag 16860 ttagtttgtt tggctaattc ataagctaat ttaagcacca aatcaatatt tccagaagac 16920 attggatata aaaaatactt acatttctgg aatcaactgc agcatacatg atatccatcc 16980 agcccttaaa tgtggcctgt tggaaaggac atgcatgcct taatttgggt taaatttcaa 17040 aactgatgct tactaatatc cttactgtac atgtttaaag aaatatttta aactattttc 17100 aaaacaaact ttccttggat tttgaaaaaa agatagaaag ccaacaaaat ggcgatctga 17160 tataacttcc tattttccaa ccagctctaa agtaactctc aagcttaaca ttctattaca 17220 atttggaaga aagtcctaga aatgtaagtg gacttggcag tgtctacagc aagaacaaat 17280 tagatctgcg atattctgtg ggaatctcgt cttctaggtg atcaagttga cagtatttaa 17340 ggtttttctt tatgcttaca gtgtatggat catatgggca taaagaaaaa acctgaagct 17400 attcttttaa gaatttttca gaaataacac tatattcatt ttctatgggg taacccctga 17460 aaagattgtg taaatataat taacaacata ataaaagtgt gacaaaatag gactgacact 17520 tgtcatttgc acattgatga gggattcctc ctctaacctc ttgcaggcat ttgtcatgtg 17580 tcttagaaca caagtttgag gctacaggac ctgaaatata tattccatag tcaatgagga 17640 agcctcgcat atttttgtga tttatctttg tatttaaatc attgactctt ggaaaatgtg 17700 ggagtgtgac cagagactaa tgtatcttag tcagaaaacg gaaattcttt tcacatcaaa 17760 gagagagatg ggtgatgtgt cagtggctta gaccaattat agaacctgtc tatcacacac 17820 ttcctacagg aacagaaaag tgatttgacc tatttctatg aacttactca tcaacagaga 17880 ggtgggcgaa atagtcaagt gtgaaatttt tacttagtag cagaacatgt ttgagagttc 17940 tgtgcactta tctggattca caaatttgta ctaacagatg ataatgctga aaacatatta 18000 taaagtttct tcctaacaaa ataacagctg caataatcac tttgttatta ttctgagcaa 18060 taaaaatttt cagagaaaat agtgttcact tacaacttga agcaaagaaa gatacccaaa 18120 tcctacatta tcaaagttta ctttcacatt tttccaccgg gcggtctcat ttctttctat 18180 tagttttagg caatcagaat gattattgac ttcgctgatc tcaaatatgt caccagttgt 18240 ggtgttaaca cagtggtaga atttgccagc aaacaaattt acgcccatga tgctgaaaat 18300 tagccagaat ataaggcaaa ccagaagcac attcatgatg gatggaattg ctcctaacag 18360 ggcattcaca accacctaat acacaaatgg agagaaagag aagtcagaat ccttattgat 18420 taaaagcaaa aagacatccc cctaggaatc attgatttat tttctatcaa gactacttat 18480 cctatctgtg taagagcaaa gcagaaataa tcttaacata aaactcagtc ttttttaaat 18540 attatgctta ggaaaagaaa tataggcaat atgcaaagag atggagaaaa gaaagaaatc 18600 taatataaaa aaggtgctaa aggaaaagca aaatgggaga agttagctcc tggatgaaga 18660 cacatgtgta gtttattaga aaaaataaaa ggaggagaga gaagtaggaa ctcctaggca 18720 agagattagc tcataaaaaa aaatcccaaa acaaaacagt atctcaaaga atagaactaa 18780 aacatttggg catgaattga ttggaccaat atactttaaa tataaattaa aattcagatg 18840 tataaatata aaactatttt taacatctaa tatatttttg gccttaatta tccatgcatt 18900 gctataacta atagtagttt ttgcataaga agcaagacaa tttagcatca tgtatttcag 18960 tagatcatca catcgtttat ttcaagctcc agtcatgtca gttgtttcat ttactgagtt 19020 taattcaata aacttatctt aaatgaaaca ctagagagat cattttctca ggaaaacagg 19080 aaaaagaggg atgtcatacg tacttatcaa ctctgatgtg actgagtaaa gtcctgtgct 19140 aaaatatttt ctccattttc taatgtcaaa gatatttccc tctctcttgt ccttaattcg 19200 ggactacaga tttaaaatgg gatttttttt ttttatattt gacatatggt agtcttggct 19260 tccttctcta tagctcacca ttgaactgca cattagtaac taagagggag ataaaggctg 19320 gccctaatgt gctcttaatt ggcaagtgtg tttcagactt gaacatggac gtcagattaa 19380 ttctactcat gttgggggag ggggggcctg ccacttttgt tagtttaatt atgaatatca 19440 tctctttgat ttttattata gtataatttt agaagttttt gcctgtctga cagaagtata 19500 agagccaatt ccttgtactt ctgagccctg gctgaacttt gtaaggaaca atatccattg 19560 gggaatacaa aatagtgggc tatgtggcca agggaaatga aaccagtaac aataaagatg 19620 agggatgaac atgaagaaga taattcagag tgcgctatca aggcagaagc caaagatagg 19680 ctgatgtgta gaaattaatg agcaactatc tccctttatg gcctccctaa aaaattagca 19740 cacaggcttt cctgtatata ttacttttta aagttatttt caatttaatt tttaaattat 19800 taagaagaga tttaaaaaca ttttaatgta attttttaaa aaattgtacc cctaaagttg 19860 tttattggat ttgagatatg aacactgaaa ttgagtagtt gtttctcatt tctgaatact 19920 tcatctccca ctcacagtga ggtgctctgt ctgccgagga tatgaaatcc atactaacat 19980 gcaagctttt cacttttaac actcatgaca ctgaacattt tggtacaagt ctgtaggttt 20040 catgctgctt ccttcaaacc tttccacctt ggccattggc cctgttctct atcttcgctc 20100 tgtcctcggt tactaagaat tacattctta tcagatttta tttgcttgcc ttctttcagt 20160 atggatacta aatttatcta tcccatgtcc cattttgaaa aattccttaa tggttctcta 20220 gccattagaa aacatttctc tttctttggc atttacatca ctcgacagtt tgtgaggtta 20280 ttttcctcaa aacagtttgc aactatgttt atttgtgtgt gcatgtgggc atgcatgcat 20340 tttctatagc acttgggtgg aggtcacagg aaaatttgca ggaattattc ctctcctttc 20400 caccatgtgg ggtcagttct ggggattgtg ctcaggtgct agacttggct gctgaaggat 20460 tctcacaagc ctgatacatt tcccctttca gcttccctaa ctggtgacat acacttcacc 20520 ctcctctgtg acagtcactc cacgctaagg tgttagtctg agaattgaga gccttctttc 20580 tttgaaactc cctgccaagt acttgccctt gaaataatct ccctcctcca ggctttagct 20640 caaatataca tgtcgtttat tgagtctaac tctacacatc cttaacaaag atgagagtgt 20700 ttgccttcga attgaggaat tataatttag tactggaaag agcaataagg acaatttggt 20760 gcttggggtt catttggaaa attagactaa tgaaggtaaa acaagttagg ttcagaaagt 20820 agaccagaat tggcatctca tactcttttc tgtttatcct gcaagttttt tcaagagttt 20880 caacctctta tggttttctc tgactgctct gtgtgaaagt taaatatttt cttatattcc 20940 aattgttaga ttatgatgct tcaatgtgtc aagtgtacat atgtgtgcaa gtgtgcatgc 21000 acatatgtga gcatatatgt ggaagcatag agctgtatgg gaaatacatg tatagatgta 21060 gaggaaagag atgtaggggt cggggggggg gattctttct tatttattgc accaactgaa 21120 ttcagagctt gaggacaggg ctagtttcat ctttctagct ctggaattac atgtaagcta 21180 ctatgcccat ccgacatttc tgagggttct ggatatccaa attccagtcc tcatacttgc 21240 ctggctaagg atttaaccac tgcataagaa agcagtttgc ataatgtaat aaatgggaga 21300 gatttccttt gaagaaggga ctggttttga attaaaagta atgcccatta gtgaattcag 21360 gatggcaaat actatatagg aatgcagttc aggaaaacgt gcaaatttgc catagatttg 21420 gcccagtgag acatttattt tacaaggatg tttgtcttag agaacatttg gcataggatc 21480 agaggatttg ccactgaaaa tccacttaaa gttgcgattt cattaacatc cagagcaaaa 21540 gatcacaaac ggattgcctc tcccaagagc ccaaccatcc cttggttcta caatattaat 21600 tctttgcagt ctctagggag agtcagtaat tggctcccat gtgggatgcg ctgggaagtg 21660 ttggtctaag tcaattggaa agaacacatt gaggttataa ggtacataaa aggagatgtc 21720 taagagagaa gtatgcttaa tgggtggatt gtagaggttg tctcttctaa caatgtttta 21780 aaaggacatc tcccagcaga atttctgtat tgtcacacaa ccagttcttc aagtctattt 21840 cttctttagg gttcatactt tttattaaat cagtgaaaaa ttaggaccag gcaaatattc 21900 ttgttgatat tagaaatttc agtgcatttg aaagtatcat ctaagtgaag acatttagat 21960 tagtttttta agtcaccgga aaccatgggt tctatagctt ttctaagaaa tagagaaaaa 22020 ccatatgtga ataagaattt aaaaaatgga aagtaaaaat catgagttct taatatgaaa 22080 tataaaaaat ttttagaaaa gccaacaact aaatcagtgt tgtgaaattt tattaagata 22140 aatatttttg atagataaat gcctcaatta tccaaacaat ttttttttct tccaaacaat 22200 aaaaattatc tttcttatcc aagactccta cattttaaga ggaagcagaa gtgtcagttt 22260 ggctttttat tttggggtgc actgtgatgc cttctaagat tctgggaagt taattggggt 22320 agcttacaag gagttggctt atacaccaat ttcttagtgc tcatgatttt tttgtttttc 22380 atgcatatcc tattctttat acttcaatga agttgacttt tcacatgttt tggttttata 22440 acttaaagca catctttttt tttttttgta ttcccttgtt tcacagggat cttgccttgc 22500 tactttctgc aaataacaca tttttatgca ataaagatga gaatgatcat aaccattggc 22560 aaccctgaga tacctggcct gttgtacctt tagccactgc tcgcacacat caacgatcaa 22620 ctgatggaat gtgactggcc cattgaggga ccagagcagt gtgttgaaaa aataaggact 22680 atatgctctg tcactaccat gagcttgaca aatgaaaacg ttttcatcag catcctacac 22740 cagggtcccc caccctcacc aattgagtaa tttccccata aatggacaat gaagtataaa 22800 tagctaaatc atattcagtg aaacgtaata aagatatgta cttctggggt tataatccac 22860 agatggtaag tcagagataa cttttttttt cccaaaagaa gtttaagctc attaaaagta 22920 gtggatttgg aaataaatcc tgtattgtcc ctactgtggt gcaattgtac ccttcccact 22980 ccctccctca atcccactac acataagtca cagtgcaagg attaaaggta gcaaaagggg 23040 taatacagta cccataataa agggctgagg ggaggaacca ccgctccacc ccatccaagt 23100 tggagcaaga ttatcctata taaaatagaa atatatagtt tattattagt tagaaagctg 23160 atatgacaga acatttggtg ttactttttg tatatgatgc tcactgcctg tttccctagc 23220 aactaagact tgagttcttt ggaaaaggtt tttacgattt tcccagcttg ggaaattaaa 23280 actacgaatt taaatacaag ttttatttga ccctaggtat tcacgacatc ggttcattcc 23340 gttcaatttc acaagttgaa aaaaaaattt ggactggaaa tttgaaatac aataaatgtt 23400 caaaagctgt cagccaaaag tgtgcataag acatgcaaaa cacaaagggc aacgtgatga 23460 taactcgttt gttactttct aactccttct caagcactat gcagcatgct gtgtttggta 23520 gtgttgcgta gaagcacatg ctttgaaaga gtgacaaaaa acccaaaaca aaatgactgc 23580 ctggttgaca ctcggacaca gcgattgcgg ttctatgctg ccaaggagga taaagtgaga 23640 gtttctgaag atactctagc tcacttcccg cttacaatca tcatcatgcc caacctcgcc 23700 gccatccaca gttatatact cttacaaagt agaaaatgtc tcatactaga aatacaaaaa 23760 ccagaatcaa cagaaggttg gttttgactt cacaatgcca aactggtggt gaggaattgc 23820 cgtgaccttg agatatttgt ggtctcacta tgtgccaagc tgaccaagga gtcagcttcg 23880 taatatctac ccagaatttt tgttttgatg actccagttt taaaaaagag aagcatatca 23940 acaataattg acaaaagcat tattaacaat aattgataaa gttatttcta cacaaaagga 24000 aaatagactc atttgttatg gaaagtcaat attacatata aaaaataaac gactggattt 24060 aataatattc taaaagatca aagttgaagt ataatctaac aaccttatat acgtagcatt 24120 attcattaaa ggcctgacac tattactgat gttatggtgt gctgcttgta ggcaggagcc 24180 tagcatggct gtcctctgag cccctaacaa cagctgacag agacagatgc caatatttac 24240 actcaaccat tggactgaag tctggatacc tgtggttgaa ttaggggaag gattgaagaa 24300 gttgaagggg agggtaactc cataggaaga ccagcagtcc caactaaccc agaccccagg 24360 gagcttccag agactgagct accaagcagg aacatacaca ggctgggcag aagcagagga 24420 ctgcctggcc tggtctcagt gggagaagat gtgtataatc cttgaggaac ttgaagccct 24480 ggggaagagg gaggcctagt gagggaggga gcatcctctc agaggcaagg gggaggagga 24540 atgagatgag aaactatagg agggggacag ggaggagagg taatggctgg attgttaaaa 24600 aatgcgaaag aaaaagaaac ataaaaaaac cataaaaagt tgaaaaatgt gaatttaaat 24660 ttagctcatg tatttttata taaaatgtat aaaaacaatg ttttccttga caactgaaat 24720 tgctattctg aaacgaaagt gctcttttaa ttggaaaagc atttaagttt tgcataattg 24780 ggagaaaatt tatgatacat ttttaataca aatgtgattt cttgtgtgag aatcaaagct 24840 cctttgtgct tacttggatc tactgaagag aagttttcat atgtgctaga gaaattaaaa 24900 attggacagg tttcttacag tatagtataa taaaatttat aataggtttt tatgggggga 24960 cacaggctga aagccctcta tgtggtgcag agaggagcct gtttgttgga gccttggttt 25020 gtaagtgtca ggacaatgag cactctttgc cttatacatt tcatctgatt ggtttaaaga 25080 gcgtaaattt tggatcttaa taaaaaaata attttcacac ggcacatctt ctataaatga 25140 ttgtataatg ctttgaaata atcatcataa caatgagcca ataaatgcaa aaatctgata 25200 cgtgttgaat tatggagagg ggaataatgc tttgctcaaa agagcaacat aaaactctgt 25260 gtaactgaga accgaggttt aagttaaggt tgacgagcca tgtatggcaa tgaataaaaa 25320 tacatgttct ttttccttat cagctgtatt gtcataagat gtgtatgtat ttatagtaat 25380 taaattagtg tcttacttat tcaatgtcat taatttagtt acagttgagg cagtattatt 25440 atactccagt caatggttaa tatctgccct tggatatatt caaataatga gaattttggc 25500 attgtaaaga caaaacattt aacaattctt cattttttcc tttgtattca tacacatttg 25560 tgattcacat tactttccat aggatccctt aagtactgat gggctgtcat agaggagaac 25620 gatatgaaac aaaattatct ctaggtaatt attacatgac tcaacttagt tctttaagag 25680 agtatctgcc cctccccctt tgtattagga attataagga aactcccaag atcgattatg 25740 aactaaggtc attttaatta gcaaagcaga taaatgatat taaatcattt tcaaagaggc 25800 cgattttctc ttgcatatca ccaagaagta aatatgcaac agagaaaagg gtaaagtagc 25860 aagtttgcaa agggttgcca ttccttttgc atgcacgtgt ttttcgttag ttaagttgaa 25920 ctcagcctag ctttgacaat atacaacgct gcagagtttt cctttttctt accctcatcc 25980 cttcaaatcg tgataaggct cttaggggtc tcagagctct tagtgtcctt agggatttga 26040 tggccccgag ttcagagtaa cccaaggcat ttgctgttaa actgaccaat gaaacctgta 26100 caatacaaat aacaatgaat caataacacc gctttcgtcc aatttgcagt tatcaactaa 26160 tacaacagat aaagttttat tcatagctgt tctgttattc tactgaataa acacagcaat 26220 agtgactcct aatgatgaac ggctttatcc atagatcact gccccaccta accctcgcca 26280 gagaagctct ctcttgcagt aggtgatggt taacagggac ccacaactgg acagtgctga 26340 gtgagagtcc ttggaaagct cagtactaaa taggatatct tcatgaaacc cctcctctca 26400 ctccttagag agctatgtgg aagaggaggc taaagagttt aagagcactt gttggcatcc 26460 acaataatgt ctgggtttgg tagctgtata tgggatggat ccccaggtgg agcagtctct 26520 gggatgtcaa caagtgcttg ctgacaggag cctgatatag ctgtctcctg agaggctctg 26580 ccagtgcctg acaaatacag aggtggatgc tctcagccaa ccattgggct gaacacaggg 26640 tccctagtga aggagttaga gaaaggaccc aagctgttga aggggtttgc agcaccctag 26700 gaggaacaac aatatgagcc aaccaggacc cccagagctc ccagggacta aaccactaac 26760 caaagagaac acatggtggg gactcatggc tccagctgca tatgtagcag aggatggcct 26820 tgtgggacgc tgttcctatg aagcttctat accccagtgt aggggaatgc cagggctagg 26880 aagctggagt gggtgggttg gtaagcatgg ggagttggga agggataagg ggttttcaga 26940 ggggaaacaa aaaaaaaggg gataacattt gaaatgtaaa taaaataact aataaaattt 27000 ttttttaaaa aagtttaaga gctagaggtg gggagtgact ccaagaaaat tagtgtcttc 27060 cagatacaac agggtgaggg acatatgagc tcacaatggt gacagacttg acggacaaga 27120 cttgtggaaa atttaaactg gactaaattg tagcgtgggg gaggggaggt gagcaggaag 27180 tttttacccc taaccaagat gctatttgat aatgctggga gagaaaaatc agttttcctc 27240 aagggagtga cactgggtat atgaaccaca ctcagggcag tctgcaagag cagaagtagc 27300 tggtctaccc aaatgttctc gaatttgatt tttgtttgtg tgctcttatt ttgttgttat 27360 tatggtttag tggttggttg ttttcgtttt tttttttttt gttgttgtag ttttttgttt 27420 gtttttgctt gtgttttatt gcttattttt ttattttctt ttttcttccc tttcctttcc 27480 tttcctttcc tttcctttcc tttcctttcc tttcctttcc tttcctttcc tttcctttcc 27540 tttcctttcc tttcctttcc tttcctttcc ttccttcctc tctctcttcc ttccttcctt 27600 ccttcgttct tcctttctgt ctgtctgtct ttctttttct ttatttctct tttttccttc 27660 cttccttcct tccttccttc cttctttctg tctttctgtc tgtcttcctt ccttctttct 27720 tttctttctc tctttctttc tctctctctc tctccctccc tctctctctc tctctctctc 27780 tctctttctt tctctttctt ccttttcttt ttataaagag aatggagttg tcaggatatc 27840 aagacaggag gatctgggag gacttggggg aaggtaagca atataatgca aaatacaccg 27900 tagaaaaatt tacactgtat gaaaagttta aaagtaataa aatattaaaa ggacataaat 27960 gaatatcaag agtaaagaat ttgcaaaata ccaagtccta accccacttg gagttatgaa 28020 agcataagct aatgcctatt gattaatttc ctctctcttt tctgtaaaac tgatgactcc 28080 tttgagattt ccatcaattt gctcactcca ttttggcctc actgagtggc cctgttactt 28140 gtttttaagt attcataact aaaattctcc ataactcact attctcaaat tctcactatt 28200 cataactaaa attctccata actcactatt ctcaaattct cactattcat aactaaaatt 28260 ctccataagg atatttggta catcaaggac tctgtaaatc tcatttacat aaaagaaaat 28320 ttcttcctca tcattaagta ggtttgtttt cccctaccct ctgtaacctt acttgtaata 28380 gacttaaaaa tctctccgta aaatcttcca gtagataaga aagatttata agattacaat 28440 agtgctcacc atcccttctg tatcttgcta ttatttacca ctggggaaga acatcaatga 28500 ataagtgcat gaagacccaa tctggagtcg gtcaagttta taacatggca gaatagacac 28560 catacctttt aaatgtcttt ttctatcatt tgcattatat attaccaata tcattgttta 28620 aatttggttt tcctactaga tcttatctcc tctttttaaa ttagttagta aattagtcca 28680 gaacttgtaa gttctatgct attattaggt gagagagttt agggctgggg agcctatctt 28740 gtcatcacaa cacagtggcc cgagactcat tcattggttt agaattggga tacaaacaag 28800 acaaactccc tcaaacaaaa ggcacgacat ggaaaatacc tacatcaaca attaagaagt 28860 ctagccaaca ccaggcattg gtgaagtatg tttgatagcc ataggccacc catttgagga 28920 gcatctccag gatgaaaatg taagtgaaga ctttgtcagc atactccagc atggttttga 28980 tcgtctttcg ctgatcaata tatatatcct caaaggccta gaaagaaaag gttacacatt 29040 ttagctttca aacactacta gaatcttaca gctagctttt tctgattata tatgcacatg 29100 gtatttcctt gggatggaag aacggggata cagtattgct attgctttgt tactctctga 29160 gttttatcct tataaaccag agagaaagat atactttaga tagctactaa aaccagagag 29220 gggggaggtg tcttcatgac ttcactcttc ctgaagtgaa atggtaattt cctgagtcaa 29280 ttggctaagc caggatgtat ttcttaatgt cacattccat gcagccatgg cgtgtctctc 29340 tctctctctc tctctctctc tctctctctc tctctctctc tctctctttg ttattggata 29400 ttttctttat ttacatctca aatgttatcc cctttcccag ttccccactc ttggaaagcc 29460 cctatcccat cccccatccc cctgcatttg taaggctttg acaggcctca taggagagag 29520 ctatatcagg cttctttcag caagcatttc ttggcattca caatagtgtc tgggtttggt 29580 gactgtatat gggatgaatt cccaggtagg acagactctg gatggccttt ccttcagtct 29640 ctgctctata ctttgtctcc atatttgttc ctatgagtat tttgttcccc tttctaagaa 29700 ggaccaaagc acccacactt tggtcttcct tctttagttt catgtggtct gtgaattgta 29760 tcttgggtat ttggagcttt tgggctaata tccacttctc agtgagtgca taccatgtgt 29820 gttcttttgt gattgggtta actcactcag gatgatattt tctagtttca tccatttgcc 29880 taagaatttc ataatttcat tgtcttaata gctgactcca ttgtgtaaat gtaccacgtt 29940 ttctgtatcc attccacttt ttgaccttag ccattctgac tggtatgagg tagaatctca 30000 gggctgtttt gatttgcatt tctcttatga ttaaggatgt tgaacacttt tataggtgct 30060 tctcagccat tctatattcc tcagttgaca attctttctt tagctctgta ccctgtttct 30120 ttgtttctat gctgtgggtg tgactcagtg gctagaacag ttgtctacgt gagaccagta 30180 gcttgacttc cagcaaaaac caaatttctc tcattattat gtttttttta taggagagag 30240 attaaatcaa taagtgattt atcaatatac tgtccaattt tattttacta agcagttaac 30300 tgcttttttg gggttttgtt gataattcta cttctttact ttttctttct tttcttttgt 30360 ttgtttgttt tgtttgtttg tttgtttgtt gtttgtttta caagacaggg ttactctgta 30420 taatagccct ggctatcctc actttgtaga gtaggctggg gctctaactc acaaacatct 30480 gtctacctct tcctgatgga attaagggtg tgcaccacca catctagctg ataattttac 30540 tttttggtac gtatagtatg acattactta ataggaatgt catattactt ttcaattaga 30600 tccacctatg ccttttccta acataaacct cagctggtaa tttacttcta atatatattt 30660 ctttcaatga tgaaaagtca tttttgtcta tgatatgcag atatgtagat aatgatatgt 30720 agaagacagt tattccatca acaattttat agaaaaatat atacttgatt ttaaaacttg 30780 taagtcattg tgttttaatc aggcaaacac ttgtgcttat ttatttatgt atatattcta 30840 tcatttatct aaatctatat atcatctatc tatctatcta tctatctatc tatctatcta 30900 tctatctatc tatctatagt ttctctatta tcaatctctc caaacatttt attttatgac 30960 ttcaatatat ttttatatct aaaattctgt caatatagtt gtatatatgt aaacaatttt 31020 catctaaatt taaatagatt ctgatgaaat taacatgttt ctataaacat aatccagtct 31080 ttaagtaatc acttaggtat ggtgcccact acttagcatt accaatatca tttgtttcct 31140 gagtagccca agaatagtga acacacatga aaagggacag agaagaggtc cccaacgacc 31200 taccaagctt ccacaaagag ttcatcagaa ctcagaggat atataaccac tataatagca 31260 ctaacatgaa ctctgatgtg ctcctcatag tcatgtttag ttaagcaaag aggaatattc 31320 actttgttta taatgactaa gcaaaaggga cccgtttttt ttgatctgtt tcatgataag 31380 caaacatcga tgaatgatta gaaatgtgtg tgcacacata gatgcaaacc cagaaatgca 31440 gctagtcatt aactatctgg caggaagata aaagggtgtt gttattgaag actcattgat 31500 aactaaggca atgggaaaca aaggcttaaa gagtgtgaga ttttcccagt tgctactgaa 31560 gcactttggg ttaaggttca ctcaccaggg caccactact caggagaatc atgaacacaa 31620 tgaaggtctc aaaccagttg tgttcaacta ttcggaagca cgtcctccgt aggttccacc 31680 actgtttccc tcttccttct tccacgctga tttgacagca cttgaatctc tggacacagc 31740 ctgcaagcat acggttccaa taggagtatg aaagatagct ctaccacctc cattatacat 31800 tgcatcagcc cagcttcatc cctccaccac cagcgctatt cctaatttgc tttaactttt 31860 aaaaagtgtg taatttataa gcaatggcaa atcaatgaaa acatacagca tcttcatatt 31920 ttgccttttc tctgacacaa tgttgccttc aaagaaaact cattgtaaat tacaaataac 31980 gacatgtagt ttgccttttg tggttgttct tttctcatct ctctcttttt ttttatttta 32040 attttaaaaa tttctttaat ccttttttat agtccagtat ttatcccact cctggtctgg 32100 ccccttactg ctcctcatcc catatttccc taccctagta tgtaagagga tgtgcccacc 32160 cacaccccac cagacctccc cactccctgg gacctcaaat ctctcaaggg ttaggtgcat 32220 tttctctcac tgaagctaga ccaggaagtc ctctgctgta tatgtgttgg gggtctcatc 32280 agctggtgta tactgcctgt tggtggctca gtgtctgagg catcttggga gtccaggtca 32340 gttgagagtg ctggtcttcc atggggccaa cctcctcctc agcttcttcc tgcttttctc 32400 taattcaacc acgggagtcc ctggcttctg tgcactggtt gggtgctagt atctgcatct 32460 gactttttat ggtctgaaat taatgcattt ggttggagct actctagaaa agggtttcaa 32520 aatgaaatta atacctggac agaaacctcc tctcctaagt gtgtattctt gtggtgctcc 32580 tgaaagggtg ttcctggttt cctaagttgt ctgagtttgc taacaggtga ctttcctgga 32640 cttgctttga tgtgtctttt acgtcctcac attgctttta tatactgaat ctagcctgtg 32700 ggcctcactc tctacaaggt ctattacatt taagccaccc actttgggtg atcgacagtt 32760 gaaaaggccg tactccgtat gaactgcaag cgatgtcacc cgcatcttta ccttcagtga 32820 agcaagcttc gggctcaagg gtttcttctg gttcaatgac aggctgttcc tctgcaggcg 32880 ccccaatgtc tactgtgctt ccctctgagg agctactgct ttcgttgagt ttctgggcat 32940 aaaatgatca taaaaagcaa attcttttaa tttaattccc caatgaatga cataccaaga 33000 agggattatt tttctcaagg taaggtgcta atgtaaattg agagtaaaac gaagactcag 33060 aagaagaggg aatgggaaaa cctaactgtt gattcctacc ccaggaattt ctgtgtgcag 33120 attgctgcgc tgtgctggga tgtcacaaat tgaccatcag caacatgtag tgagggaact 33180 cctatcccat ggattgggga aggagagagt gtcgtgactt gtaggaatgg ggagagagat 33240 aagggaaatg aagctcggag aatctctacc tgagaagaaa ataaaaccat taagctagtc 33300 tgtgtttaaa catttacata tgtttctcta atagtgtctc aattctgaga aattataaca 33360 taatgcttta acttacactt cctgttagaa cagaggatca gaattattta ttataaatgt 33420 attcatattt ttatatttca tatgcctttt ggagaaaagg tgttttacaa taagttaaaa 33480 atacatcaat aaacaaatag ccttagactc ttaattaaag gggttcatta ttggaaaata 33540 ttttcgaacc taaagtgttg cagaaacaga ccaataaatg catggaaaag tcagtttccg 33600 ctcaacaagt aacacactaa tatcccacgt aaagctaatt caacagaaac agcgtttctc 33660 agactttggc agtagtcacc agacacatgg tgctctttgg atccttagga gtcaaagatg 33720 gcaaaaacag cagaaaatat caacttatcc tgctgacctt caaattgttg taagagtaaa 33780 tagtacactt ggcaatttag tcaagttaag atacactgag cgccaacaat gtgctagaaa 33840 cttggtgttc attggcaact ataaaatccg tagccctatt agatacttga aataaaatac 33900 gatgtttttc aaacgatgga tttatgttta atctaaaaga gatctcacca actacccagt 33960 caacacatat ttttaaataa taaactttaa gcatcatgct aaaactacta ctactaattc 34020 gtatacatga aacagttttc tttgttccat caaaggaaga tggcttctac acctgggcct 34080 ctatccagct gactgtctct cttcctttta aatttcttgt taaatagaaa attaaaggtc 34140 acaaggatct gcattgacat gaaagaccag tcatggttct gagtgtctgt tttaaagatt 34200 acctctgtta ttatacatag attcttcact ggaagctagt tttaagtttt taaataatta 34260 tgactatagc acgtttacat attcatcatc tggagaattt gctcctctgc acaggataca 34320 gcaacaggta gactttaaat ctacactgca tttgctttga atgattcaac catttcttct 34380 gacttaaaaa catatccaag gataagtcat gcatttggcc atataataag tgaagagact 34440 ataataaatg gctagtctgt gtgcttgagt tacagtgccc attctgagga ttcctgtgtc 34500 tttcctcaac ataactggaa tctataattg gctgtaatgt gctacaagaa ttatttctta 34560 tttcctaaaa aaaaccctgt gagtagaatt ttatcattat ccagcattct tcttcttctc 34620 ctcctcctcc tcctcctcct cctcctcctc cttcttcttc ttcttcttct tcttcttctc 34680 cttctcctcc tcctcctcct cctcctcctt ctctctctct atatatatgt ctgtctgtgt 34740 gtattctctt tgtataataa gtaaattgat ttgagaagtt aagagtcctt accaaaattc 34800 attaattact agaaatccca tcttcctccc tctgaataaa cttatgtgtg ggcagggatt 34860 cagataaact ttattgtaaa tagaaatttt aacttgctga gcatgtaaca gtgatctgtt 34920 agatctctac agatattttg ctctctgtca agaatcacaa tatcaggtac cattcagata 34980 aaacctaatc ttcagtgata tcatttttca gtgtcaagta gaacaaaacg ctctcaagca 35040 gcctttctac aacaatggca tttgctagta agatactgca tatagctggt tctacgtctt 35100 gccagccata tcatgttttt cacaatgacc actgttttca ttgacgtgtg aagtactgac 35160 ttcttattct acgtttaaaa gattacttag ttgatggaac taaatactat ttttcttgtt 35220 ctaagaaaaa ggagtctgaa caggtgagag ggtgcgccac agaaccggat agcttctggg 35280 acaggcggag gcacagagcc actgaggcag catcctttgc gggcagcaga cagccggcca 35340 ccgtctggac aagaggacag gtgtccgcct ggctcagaag gcagcctcag cctaaggagc 35400 agctgtcgcc atcttggttc cgggactccg cagaacctag gaaattagtc tgaacaggtg 35460 agagggtgcg ccacaaaacc ggacagcttc tgggacaggt ggaggcacag agccactgag 35520 gcagcaccct ttgcaggccg cagacagccg gccaccgtcc ggaccagagg acaggtgtcc 35580 gcctggctcg gaaggcggcc tcagcctcag gagcagtggt cgccatcttg gttccaggac 35640 tctgcagaac ttaggaaatt agtctgcaca ggtgagagtc tgcaccacag aagctgacag 35700 cttctgggac ctgccaaagc aacacagctt ctgagaaagg tcctgttttg ggccttcttc 35760 ttcggccagg aggaggtcca aacacaagat atctgcgcac cttccctgta agagagcttg 35820 ccagcagaga gtgctctgag cactaaaact cagaggagag aatctgtctc ccaggtctgc 35880 tcatagacag taacagaatc accagaagaa caatctctaa acagagtcaa ctataactac 35940 taactccaga gattaccaga tggcgaaagg taaacgtagg aatcttacta acaggaccca 36000 agaccactca ccatcatcag aacccagcac tcccacttcg cccagtccag ggcaccccaa 36060 cacacccgaa aacctagacc cagatttaaa agcatatctc atgatgatgg tagaggacat 36120 caagaaggac tttaataact cacttaaaga aatacaggag aacactgcta aagagttaca 36180 agtccttaaa gaaaaacagg aaaacacaat caaacaggta gaagtcttta cagaaaaaga 36240 ggaaaaaaca tacaaacagg tgatggaaat gaacaaaacc atactagacc taaaaaggga 36300 agtagacaca ataaagaaac tcaaagtgag gcaacactgg agatagaaac cctaggaaag 36360 aaatctggaa ccatagattt gagcatcagc aacagaatac aagagatgga agagagaatc 36420 tcaggtgcag aagattccat agagaacatc ggcacaacaa tcaaagaaaa tggtaaatgc 36480 aaaaagatcc taactcaaaa tacccaggaa atccaggaca caatgagaag accaaaccta 36540 cggataatag gagtggatga gaatgaagat tttcaactca aaggaccagc aaacatcttc 36600 aacaaaatta ttgaagaaaa cttcccaaac ctaaagaaag agatgcccat gaacatacaa 36660 gaagcctaca gaactccaaa cagactggac cagagaagaa attcctcctg acacataata 36720 atcagaacat caaattcact aaataaagat agaatactaa aagcagtaag ggaaaaaagt 36780 caagtaacat atataaaggc aagcctatca gaattacacc agatttttca ccagagacta 36840 tgaaagccag aagagcctgg acagatgtta tacagacact aagaaaacac aaattccagc 36900 ccaggctact atacccagcc aaactctcaa ttaccataga tggagaaacc aaagtattcc 36960 acgacaaaac caaattcaca cattatctct ccacgaatcc agcccttcaa aggataataa 37020 caggaaaaaa aaaaaaaacc aatacaagaa cgggaacaat gccctagaaa aaacaagacg 37080 ataatccctc aacaaaccta aaagaagaca gccacaagaa cagaatgcca actttaacaa 37140 caaaaataac aggaagcaac aattactttt ccttaatatc tcttaatatc aatggtctca 37200 actctccaat aaaaagacac agactaaaaa actggctaca caaacaagac ccaacatttt 37260 gctgcttaca ggaaactcat ctcagagaaa aagatagaca ctacctcaga atgaaaggct 37320 ggaaaacaat tttccaagca aatggtatga agaaacaagc tggagtagcc atcctaatat 37380 ctgataagat tgacttctaa cccaaagtca acaaaaaaga caaggagggg cacttcattc 37440 tcatcaaagg taaaatcctc caagaggaaa tctcaattct gaatatctat gctccaaata 37500 caagggcagc cacattcatt aaagaaactt tagtaaagct caaagcacac attgcacctc 37560 acacaataat agtgggagac ttcaacacac cactttcacc aatggacaga tcatggaaac 37620 agaaactaaa cagggacaca agtgaaacta acagaagtga tgaaacaaat ggatctgaca 37680 gatatctaca gaacatttta tcctaaaaca aaaggatata ccttcttctc agtacctcat 37740 ggtaccttct ccaaaattga ccacataata ggtcacaaaa caggcctcaa cagatgcaaa 37800 catattgaaa ttgtcccatg tatcctatca gatcaccatg cactaaggct gatcttcaat 37860 aacaaaataa ataatagaaa gccaacattc acgtggaaac tgaacaacac acttctcaat 37920 gataccttgg tcaaggaagg aataaagaaa gaaattaggg acttcttaga gttcaatgaa 37980 aatgaagcca cttcataccc aaacttatgg gacacaatga aagcattcct aagaggaaaa 38040 ctcatagctc tgagtgcctc caaaaagaaa ctagagagag catacattag cagcttgaca 38100 acacacctaa aagctctaga acaaaaggaa gcacattcac ccaagaggag tagaaggcag 38160 gaaataatca aactcagggg cgaaatcaac caagtggaaa caagaagaac tattcagaga 38220 atcaaccaat cgaggagctg gttctttgag aaactcaaca agatagacaa acccttagcc 38280 agactcacta gagggtacag ggaaagcatt ctaattaaca aaatcagaaa tgaaaaggga 38340 gacataacaa cagatcctga agaaatccaa aacaccatca gatccttcta caaaaggcta 38400 tactcaacaa aactggagaa cctggatgaa atggagaagt ttctagacag ataccaggta 38460 ccaaagttga atcaagatca ggttaatgat ctaaacagcc cgatatcccc caaagaaata 38520 gaagcagtca ttaatagtct cccaaccaaa aaaagcccag gaccagatgg gtttagtgca 38580 gagttctatc agaccttcaa agaagatcta atcccagttc ttcacaaact attccacaaa 38640 atagaaacag aaggtactct acccaactca ttctatgaag ccgcaattac tctgatacct 38700 aaaccacaaa aagatcccac aaagatagag aacttcagac caatatccct tatgaatatt 38760 gatgcaaaaa tcctcaataa agttcttgct aatcgaatcc aagaacacat caaaacaatc 38820 atccatcctg accaagtagg tttcatccca gggatggagg gatggttcaa tatacagaaa 38880 tccatcaacg taatccagta tataaacaaa ctcaaagaca aaaaccacat gatcatctcg 38940 ttagatgccg agaaagcatt tgacaaaatc caacacccat tcatgataaa agtcttggaa 39000 agatcaggaa ttcaaggccc atacctaaac atgataaaag caatctacag caatcccact 39060 aaaatcaggg actagacaag gctgtctact ctctccctac ctattcaaca ttgtacttga 39120 agtcctagcc agagcaatta gacaacaaaa ggagatcaag gggatacaaa ttggaaagga 39180 agaagtcaaa atatcacttt ttgcagatga tatgatagta tttataagtg accctaaaaa 39240 ttccaccaga gaactcctaa gcctgataaa cagcttcagt gaagtagctg gatataaaat 39300 taactcaaac aagtcaatgg cctttctcta cacaaaggac aaactggctg agaaagaaat 39360 tagggaaaca acacccttct caatagccac aaataatata aaatacctag gcgtgactct 39420 aactaaggaa gtgaaagatc tctatgacaa gaacttcaag tctctgaaga aagaaattaa 39480 agaagatctc agaagatgga aagatctccc atgctcatgc atcggcagga tcaatatagt 39540 aaaaatggct atcttgccaa aagcaatcta cagattcaat gcaatcccca tcaaaattcc 39600 aactcaattc ttcaacgaat taaaaagggc aatcggcaga tccatctgga ataacaaaaa 39660 acctaggata gcaaaaactc ttctcaagga taaaagaacc tctggtggaa tcaccatgcc 39720 tgacctaaag ctttattaca gcgcaattgt gatcaaaact gcatggtact ggtatagaga 39780 cagacaagta gaccaatgga acagaattga agacccagag atgaacccac acacctatgg 39840 tcacttgatc tttgacaagg gagctaaaac catccagtgg aaaaaagaca gtattttcaa 39900 caaatggtgc tggcacaact ggctgttatc atgtagaaga tttcgaattg atccagtact 39960 atctccttgt actaaggtca aatctaagtg gattaaggat ctccacataa aaccagagac 40020 actgaaactt atagaggaga aagtagggaa aagcctcgaa gatatgggta caggggaaaa 40080 aatcctgaat agaacagcaa tggcttgtgc tgtaagatcg agaatcgata aatgggacct 40140 cataaaattg caaagcttct gcaaggcaaa agacaccgtc aataagacaa aaagaccacc 40200 aacagattgg gaaaggatct ttacctatcc caaatcggac aggggttcta atatccaata 40260 tatataaaga actcaagaag gtagactcca taaaatcaaa taaccccatt aaaaaatggg 40320 gctcagaact gaacaaagat ttctcacccg aggaataccg aatggcagag aagcacctga 40380 aaaaatgttc aacatcttta atcatcaggg aaatacaaat caaaacaacc ctgagattcc 40440 acctcacacc agtcagaatg gctaagatga aaaattcagg tgacagcaga tgctggcaag 40500 gatgtggaga aagaggaaca ctcctccatt gttggtggga ttgcaggctt gtacaaccac 40560 tctggaaatc agtctggcgg ttcctcagaa aattggacat agtaataccg gaagatccag 40620 caatacctct tctgggcata tatccagaag atgccccaac cgataagaag gacacatgct 40680 ccactatgtt catagcagcc ttatttataa tagccagaag ctggaaagaa cccagatgcc 40740 cctcaacaga ggaatggata caaaaaatgt ggtacattta cacaatggag tactactcag 40800 ctattaaaaa gaatgaattt atgaaattcc tagccaaata gatggacctg gagggaatca 40860 tcttgagtga ggtaacccaa tcacaaagga actctcacaa tatgtactca ctgataagtg 40920 gatattagcc cagaaactta ggatacccaa gatataagat ataatttgct aaaaacatta 40980 aactcaagag aatgaagacc aaagtgtgga cactttgcct tcttagaata ggaaacaaaa 41040 cacccatgga aggagttaca gagacaaagt ttggaagtgt gatgaaagga tggaccatct 41100 agtgattgcc atatccagag atccatccca tgatcagctt ccaaatgctg acaccattgc 41160 atacactagc aagattttgc tgaaaggacc cagatatagc tgtctcttgt gagactatgc 41220 catggcctag caaacacaga agtggatgct cacagtcagc tattgaatgg accacagggc 41280 ccccaatgga ggaactagag aaagcaccca aggaactaaa gggaattgca accctatagg 41340 tggaacaaca atatgaacta agcagtaccc cggagctctt gtctctagct gcatatgtat 41400 caaaagatgg cctagtcggc catcactgca aagagaggcc cattggactt gcaaacttta 41460 tatgccccag tacaggggaa tgccagggcc aaaaaggggg agtgggtggg taggggagtg 41520 ggggggtatg gggacttttg gtatagcatt ggaaatgtaa atgagctaaa tacctaataa 41580 aaaatggaaa aaaagaaaaa ggcttatctg agaaatgcct ggaatgaaaa ttgcaagaac 41640 ccaaaaggca ctatgttatc ttttgacaca ttttcaaaat atcattttat gtagaaggca 41700 aatagatatg cacttcaaaa aattcattta gactgtattt acattcatat ttcacatgtt 41760 gactttttta ggctacctac ataaaatttt cactcttcca aagtctttgt aaagaatata 41820 tgcagactga cagtttttcc ttgttatttt tatattggca tcttaattca taaagatagt 41880 ctgaggctta cattatttct attcaaactt tattcttttg agttgtcgaa atatttcttt 41940 ctagtgagga tataatggga cagtaagaca aaaaaataaa aagacaacaa acactggtgt 42000 gtacaaactc aaccaccttt actggaattt tggttacata aaggcctaat ctccttattt 42060 ttaaatgcaa ttctgtcttc tgacttatat tttaccttca gtttaactga cctgaggtca 42120 gatagccata tacaatatct gctatcttga ttttctaagc tttactttga gttccgatat 42180 actgttcctt tttgtaaaca tctatggata cttgtggata atactaacat taaaaatact 42240 agtaatgggc tacagatggt tcagcggtta agagctctga cttctcttcc agatgtcctg 42300 agttcaattc cccgcatcca catggcagct ctcaaccatc taaaactcca gttccagagg 42360 ttctgacgcc ctcatctgat cttgtgggaa gaagatatgt aagtagtaca cagatagaca 42420 taaaagcaaa tactcatgtg tgtgcatgtg tgtttgtgtg tgtttgcaag tcttattata 42480 tgaaataaaa taaaggagtc tcaatgtcgt catttaattt gttacatttt aatcatgaga 42540 taaaacattg cttcagaact ctaaaagcaa aggtatgctt attattattt atctcattgt 42600 taaaacaaaa agtaagtgca gttctttggt taagttatca ctgctactca aatagggagg 42660 aagctcaata gctctgaggg aggggctcac ctcaactttg cacacagaca tgtttcatac 42720 aatattctaa agatcctagg taacaatgca acccagtgtt gtcaaacaag tattttatta 42780 ttttaaaact taatgaagta gactagttcc tttttattct taagttggta ttaatttttg 42840 ctttttaaag tatgtttctt agtgttttga aattaataaa atatgttaaa tccattttag 42900 catttaatat gctattaatc aatcttcaat ttattaattc cctaatggac tagttaatta 42960 gaggctgggt atatttttcc atataaaccg tctgatctgt gcaatccata tgtacttggc 43020 aggttattta tgaggtgaga tgatcagtta ctaactgcga ccctgatggt aagagcattt 43080 tcccttcacc gtggattcat gctccctttt ttttcctttt tttttttttt ttgcttttaa 43140 agatgttctc tggtagagaa aatgaccttg aaaatgaaac aaaacaaaac agcaacagaa 43200 caagccacag cttggggttt ctttggaagg aaccagtcag gtgtctcttt cttctcagct 43260 ttaactttaa acgtgagatg tctttatttt gtgacctagt ttattacagg gatattatta 43320 atgtatatta atgaaagttt actttttatt tttaagattt attattatat ctaagtacac 43380 tgtagctgtc ttcagacaca ccagaagagg gcgtcagatc tcattacgga tggctgtgag 43440 ccaccatgtg gttgctgggg tttgaactca ggacctttgg aagagcagtc agtgctctta 43500 ccccctgagc ccgaaagttt actttttaat aagtgataaa aataattggg attttgtaac 43560 tgatgggtca tatagtgcac tgtcatatgt acagagagag agatgcaaca aagactagca 43620 cggaaggaac ttatctataa atgaagccca tactcatcta tgaacaaagc atgacgtgtt 43680 tttaacctta gcctttcgct gacttgatac ttttatacaa aaatatataa atgagattcc 43740 tgatgctctg tttatcagtt attattgtct caaagggtta aaatacttgg caaagcagtt 43800 taaatggaag aacgttttct tttggctcat agtttctgag caggcagtgc atgatggtgg 43860 ggagagagca tgttggttta gagcagtgca tgtcatggtg agcaagaaaa ccaagaaagg 43920 gaaagcagcc tctgctggta gtcatcattg tcgtcatctt cgtcttcttc ctcctcttcc 43980 tcttctttct ccccctcttc ctcctccccc tcctcctctt cctcctcttc ctcctcttcc 44040 ttttcctcct cctcctccac ctccttctcc tcctcctact cctgctcctc ctcctcctct 44100 tccttcttct tcttcttctt cttcttcttc ttcttcttct tcttcttctt cttcttcttc 44160 ttcttcttct tcttcttctt cttcttcttc tccttcttca tttcttcttc cccctctcct 44220 tttattattc agtctgtgct cccagtccct gggtgggtgt catttccatt taaacatagt 44280 tttcttctta gttaaccctt tatataaact ccctaataga tgtactttgg ggtgcacctt 44340 acagttttct aggtggttct acatttagcc aagtagacaa tgcagattag ccatcatact 44400 ccatagcatt aaatatatga atgttaatat gttgttgtgt atattctgcc ttaggagata 44460 tttctaatgt atgcattaaa atcaaaatga tcactattaa tgactctcaa caaagcaaca 44520 ctgtcatatc aaagaaaaag acactattga gacagtagtt cttataaagc agcagggaag 44580 ctcaaacacc agcccttagt gccccatatc atcagtttcc ctaatgtcgg tctctactac 44640 cctaacttct caatataaag acaggtggta ttctccatac accctgtttg ggtactagca 44700 caataggcaa attgcattga cacaatctat tctaatatac taaaatttaa aaaaaatggg 44760 gtaacatatt ggcttttaaa ctctaactgg gcgatggctt gtaatttaga aacattacat 44820 ctctaatgtt tatactattg taatatccat gatttttaaa tcagcagatt tctgagctac 44880 aagagcatgg gaaaagaatg gctatgggct ctaggggttc tgtggacaat cagtgatgaa 44940 gatgtcagtg ctctttctat tcctgattaa tgcaaacaga agctgtacaa atgcgaatca 45000 tgttaatttt cagtggaaag ataattttat ggatactttt tacaatacaa ttgcttatca 45060 gtaatattca gtacataata agtagctgct actattattc agccaatatt aaatgtacgc 45120 ctatagattc aaggacttaa gatgaggaga ttcaaactag aacgaatttt ggaaatttat 45180 cttgtcagaa atttagaatg atgtgtttaa ataagatgtt ttgttgatat ttttactttt 45240 agatgtgatc ttatatgttt caggcttccc tgaagctcac tatctagctg agacgttgag 45300 ttcctgatct ttctgacttt acctgcccaa tgatgggctt ttagtcatta ggtaccatgc 45360 tcaacaaaca tttatttcac agttgacatc taccatttat ttcctagaaa acaccaggta 45420 ctaagtaaac attttaaata agacaatgtt cacatagtag tccttaagac attcagtaag 45480 ttaaaaaaaa aagtccatct tcctcccaca ctaaatccat ctcattggag ttagtagttt 45540 ccccactgtc tcacttctgt gttattttgc tttctcttct ttcacgagaa gaccccaaaa 45600 tatctcaatg cagccactgc tagttttaat atcagttcct acttctaaaa gtgggaattc 45660 caatatgaca ccaaagtttt tataaaagct tgaatcatca ttaaatagac atattcaaca 45720 acctaatatc atgtcatgtg tctatgcttt ctgctctagg aactaccaac caaaacacac 45780 cattgtttcc cttgcttatg gttgatatac cagtcgattt ttaataggaa tagagtatct 45840 ttgaatagag tgtctttaaa gtatttagat tactcaagct ctaaatatgc tttgttatct 45900 ttgagacttc catgcaatag cattatatca cagaaatccc actgtaagat gaaaatgtag 45960 ttagagaaaa aaaaaccatt caggacacac aaaccactga acaccatagc tagcaatata 46020 cacaggaatg tgttggttgt tcagaaatag taacggtaag ttagcccaag ttagagacag 46080 tcctaatatc cacaaatgtt ttagctttaa tattttcaag taggacctca tggactgaat 46140 tacattcccc tacccattct tctatcctaa attcaattgc tgaaactgag agtctctaaa 46200 tatctgaagg tctggcttga taatgagctc tacttatcta atgactccaa gattctcatc 46260 caatagagta attcccttac aagttgagga agagacaaga gatccatttc tgttcagtgc 46320 acctatcagt caggccttgt aaagacatag tgagaaggtg gacatctaca accttagcaa 46380 atagtcctcc ccagacactg accctgcagt accatggtct tgaaatgtct gctttccaga 46440 ttgtgaataa attttttttt ttgtgtgtgt gtaagccatc tatttcttag caccatgcta 46500 ttttatgaca ttatgtaatt ttaatgtgac aattggtagg gagcactttt tttctgaagt 46560 tcactcagtt atttaaactg agatgacaca cacaaaaata ttaaaactta aagacaaagg 46620 cttcaggttc aaagtggggt tccacccctc acaggttaca tgctcttagc cagccaaagc 46680 tggttgtttt tttcttttgt tttgttttgt tttgtttttt cacttgaaac tttacagtaa 46740 tatgttcctt tctgttcatt acaaggatta agtaactaat gatgctagtt tttaattcat 46800 tatttgtacc catttaacaa acagatttta agaatgagaa aactcataca acagtatatt 46860 acattttgct ttggcattca tctccctgag aaaagatttt tggaatctca ataaaataat 46920 atttgatatt atatcaaaaa ggttctatag aatcattaat acagaaagta taatccatac 46980 atatatttat acatatacat ctccccaatt tacagcatct tacctctttg ctttcttcta 47040 gatctgattc actgctaaag tcttctgtgt ttaagttctc aaagtcagac tctcccacag 47100 caatgggcac agtcacagtg aggctggggt tgtttatgaa tgacatataa tcactctcat 47160 caatgatgta cttctccaca ctgctgcccg tccctatgcc acttgtggtt ccattcacat 47220 ctttcagaca gtccagatct ttcccaattt ctgttgtgtg gttagagata caattgtctt 47280 ttctgttgtt tagatcatca agtggcttaa tttcatctag aatcttctgt ttcttaacaa 47340 aggattgttg aatgaattca tatatttttc tttttacata agctattcct ttgtgcatcc 47400 tgtccacagc aatctgcagg ttgttcatct cattgtcatc atcagtggct gcaaggttgt 47460 ctgcactaaa tgagctcaga agcaaggcca gaaagaggtt caagaccttg aaaacagaca 47520 taagtatgtg ttcaccacaa cacagaggac ataggatggc ttattccttt agctatagaa 47580 tgaataaccg aatgctatat gagcaagata cagcacaggc attgctagaa gttaagtggg 47640 ccaagaccag aaaacatgag gccctgggtt caacactccg ccctagaaaa gttttgagca 47700 ctctgaattt gtgatattgc tccatctcta tgtacatgag gcattctttc tactgctctc 47760 aagatctccc atacatgaaa tgaagaactt gaatgaatta gtttatcatt atatttaata 47820 ttatatgagt aaaagaagat atatttactg agatacttta acaattccaa atttaaaaat 47880 gattaatatt tgcaattatt tatttaaatg tattttgggt tttctctctt catgattttg 47940 tgttgttgga tgataactga aaaaaatcat agtcatgacc aaatttagaa tgaaagtctt 48000 caacatatgc atggaccatt cttgttagca ctattctata gcaaaaattg ccccctttct 48060 ccctcacatg cacacgcaca catagacatc acacacaaac acacgcacat aacatatttg 48120 tgtaaatttt taacagtcct atgcaattta ataactaaat gcaatgaagt gactgaataa 48180 aatagagttg agaagccagg tggcacaatc actttaatcc aagtacttgg gatggagagg 48240 caggtggatc tctgagttca agcccagcta gatctacaga gcaagttcca ggacagccag 48300 ggatacagaa agaaaccttg tcttaaaaaa atagagctgt aaaatatgga tttgagagta 48360 aaatatcata ggtaatatta atgtgcatac atttgtttta agatgtattt ctatattacc 48420 atagtagatt gtgatactat actttgccat gttgcggtat atttttagaa taagaagata 48480 aacatatctt aagatcagag gcatttaaaa ttatttatca tgaaagtcat tttttaataa 48540 attgggcaca aatttgttat gttattgatg tatttctgaa atgcatatct aacttgggta 48600 cataccacaa ggttcccaat caccatgacc atcatgaaga cagtaaggca catagcttgt 48660 cctgccacct ccatgcagtc ccacatggtc tctatccact ccccacacag cacgcggaac 48720 acgatcagga acgagtggaa gaagtcgttc atgtgccaac gtgggagttt gcagtcagtg 48780 gcaattttgc agacacaatc tttgtaactt tttccaaaca gctgcatgcc aaccacggca 48840 aaaataaaga caatgatggc caacaccaga gtcaggttgc ccagtgctcc caccgagtta 48900 ccaatgatct taatgagcat attcagtgtg ggccaagact ttgccaactt gaacactcgg 48960 agctagaaaa tgagaacaaa ttaatataca ttattatgat cttcacaagc attaattatc 49020 ttgagactta ctaaagaata aggggctgca gctcagagac agaacacctc cttagtgggc 49080 atgcagccat gagatccgtt gctagcacta cacaccccta aaaaattctg cttacattat 49140 cttgctctaa ctttctcagg ttcatagtta atatttagac cctcatagga agaatctagc 49200 ttttccagat tttaataatg tggctcatct tctctgaaag tgatttccta gttgcatatt 49260 agaaactata ttctttaatt tgtttctctg agaccatctt ccaagtttta tagtgtcata 49320 ttgatatctg aatgtgaata atttctgcca aaggattcat ttgtcaaaaa ggttctaagt 49380 aacattgcat tgagagcatt gatgaaaata aaatgaaaaa tatttattat ctattaatat 49440 tataacagag gaaaaatata aataaatgca atgtattgtt aaacctggat tatttgctat 49500 gactcttcct caatcttcag ggaatttgta tgaatctatc tatctatcta tctatctatc 49560 tatctatcta tctatctatc cttaatagac ctgcaaactt ttgtttttat ggaacatatt 49620 ttttagaagt agaattacat gcatacattt tatgtgaata tcgaagagtt atttacattt 49680 tcaacattta ttaagttatt aaccatttct attaaacaca cttcttcagg ttgaaagtat 49740 taattgtcca agtcattaga aagaacacat tatcaacaca gcaatagaaa aagatatcag 49800 tgttcacgtg acggggctag tgacagctca aggctctggg ttatgtaacc cagcactgca 49860 aacttataaa tgataatatt agaaagttta cataaatagg cttttcagaa gaaagttgcc 49920 tttgtaaaaa aatatacaaa tattacctga gagatattat tccccattta gaggtatcag 49980 cctacacaaa aacttaaaat gataatagtt ttgtggaaaa gtatagggaa gcactatgag 50040 agaacaccac tggggaaaac agttattatt gcagttgtct tgtttaccag tcgaaatgaa 50100 cggagaactg acaatccttc cacattggca aggccaagtt ctaccaggct gagtgtcaca 50160 atgaaaccat caaagatatt ccagccttct tggaagtaat agtaaggatc cattgcgatg 50220 attttcagga acatttctgc tgtgaaaatc ccagtgaaga cctaaaagca aaaccatatt 50280 atttaaatta tcttagatag tgataacatc aaagataata ttatatatat atatgtatat 50340 acatatatat atatatatat atatatatat atatatatat atatatatat atataaaaga 50400 ctaatgctac ttctactttt ccattattga tcctaagatt atcctacaag tttatttgac 50460 aatgctggtt tatattagtt tactgtttta tgctcataga agctccaata accagatagt 50520 gtaaatgctg taactatttt attacagatg aagagaacaa tatttcaagg tatataaaat 50580 gcccatctat tattaaccaa cttccagacc tcatgtcacc tagacaagat tttgccccaa 50640 aacattttat ttgtaagttt atctttattc ccttcaaatc atgtgtatct tatattattc 50700 tcatcactat cattaatatt agtcacatgc actaaaagtg cgtttccaga atctaaatag 50760 tagagattta aaaatataaa tccactatag catatgcata tttacattgt ctttatcagc 50820 aagatactaa acattctcct agatattata tagaatgcat gttatacttt agatagttct 50880 ttcttcaaat aaaaacctga gacttttaag ttgagtctgc tggaaaatat tttaacaatt 50940 tatgcttcaa agtaaaaaat ggagaatatt gtcgaaactt tcactaaaaa tgggcttact 51000 aatcatatga tgtacaaaat gcactaggta ctgtcaatat ttcatgatat gaatctagaa 51060 cagaacttag actcccttga ccctggaagg aaaaaagatg gagacacttt tgtgttatca 51120 ttctttgaaa gagcatataa ggaagagaac tcatgacctt atttgaacca tctggagcta 51180 ggacagagtg atcttatcat ttaaagaaga acatggcctt agattctgaa agaacaccat 51240 tactgacttt ttaaattatt attacaggtc tatgttctat ttctcagttt ttgcacagac 51300 attaaaggcc attatttggc aaaaggtagt gtgtacccgt ctggatatta ttgccttagg 51360 gatgcaggaa ttgtggttga aagaggtcta ataaactatt gaagataata aacagtttct 51420 taagcagaaa atttgaagac caagctcatt tatttacctt cttgcacact taccaagttt 51480 cccactgtaa gaacatggtt gaaatgttca gtcatggggt agtgctccat agccatgaag 51540 agcgtattta acacaatgca gatggtaatg gccagatcaa caaatgggtc catcaccacc 51600 aggttgacaa tatgtttaac tttcagccaa tatggagaac agtcccaaat taagaatatg 51660 ttggaaaatt tataccaaca gggtggacat ttctgcctgg attcttctag ttctagattt 51720 aaaaaaaaaa tagaagaaac aataaccaat tatttgaacc atctagagct aggacacagt 51780 gattctatca tttaaagaag atcatggcct tagattctga aagaacacca ttactgactt 51840 acaaatttac aaatttattt tagatccact aaacatgctc tcagtagcaa acatatttct 51900 ctttgctgca aagataatta cttgataaaa tggtacagta tcattagtca tgtacataga 51960 gataggaaag aaaacttttt gttttgtttt tgcatagaca gtgttgctta acacttggcc 52020 tctattacag tggttgggca tatagacaaa ggttccatgg aaacatagcc tggaactatt 52080 cactctgtgt aaaatttctt gttactgata ggctacacaa ttttaagatt taggacaagg 52140 attaatgtaa tatataaaga aatcattctt tatgctttga ttttgtgaaa gtgacttatt 52200 cttttctcca gtcttaaaat tatttcagat cataatgtaa ggggccatgc tgctgaagtt 52260 tgaagcacat tacaacaaag gatttgtgac taatggatta gaaacctcta gctgttccca 52320 catacttatt aagacattaa aagttcagaa gtttagaaca ttgaatttag tatgtaatac 52380 tttcagaata catcaccagc catttgctag taggactgtt ccttttactt ttgttcatag 52440 agtgtacttg ccaacacata agtagagaga gttgactcca acaagatatt gcaagatggc 52500 tgaactgagg gaggtagggt ttgttaccaa ccttctactg tatttgttaa gatgctggct 52560 atgctcattg ccctttgcct ctgggaagga tcttctagaa agtccatgga aacatggaaa 52620 gagctcgacc tcctctttct catctcagtt tcagtggttg ttccctgcaa agcaaatgct 52680 aaggcattac atgactagct tgagcaatac agcacagaaa taaatggaga cagtgatttt 52740 catgaaagac atgcgtcatg cgtcttcatc tttgatggcc aatggcagat actggtgact 52800 tattggatca ttaacctgga atattcaaac agttaaccat gtagtcataa aggaaaatat 52860 aaaattttga cccctccttg attttatact cttatgaaat aggatgcgat caaaatatag 52920 ttagtaaagc tttgcatagg catttatagc ttgttttcaa ttaatgaaca tactgtcaaa 52980 tcttaatgcc ttaaaatctt atatatggtc aggccatttt tcactttcga gaaagtagct 53040 gtttaatttt aagaaaatac cgaagaccat aacacactta gctgtcatct caatttctaa 53100 gcataagaca tatactcatt tattataaag tatatgctga tccatgcatg tgatgcaggg 53160 gcaacagttt catccaggat accaaagcaa taagtcatct gatttacacc gagtcatgcc 53220 tcgtcatgct gatatatttc caattatttt atctggatta ataatttatt ggtgtctctg 53280 tgtagattgt tttgtgaata cctatatcag catttctttc ttagtgagat aaatatgatc 53340 cttagaaaat gtaggtaatg atgaagctat ctaagcacag tgtttttgaa aatctgaact 53400 aaagcccaga taaactgtaa gagtttagtg ggaagattta ctatacaccc tttacactaa 53460 aaagtcattc atttaatctt acaataatag ggcactaggg gtgatgtctt catatgtaaa 53520 ttcggtatgg gtacatagca aatcatccaa ggaagtaatt attgttcaat taatccttag 53580 catatacagt aggtaatgca ttcaggtttg tgcaaggagt gccgaggcgc taacatttag 53640 ctggttagtc tattaaaggt gctacaagat gcaggtgcat tctcagctcg accaaccagg 53700 aatcattctc aagagttcca ttctgtagaa acactggctg gtgcagcaat cataggccag 53760 ccatgcctga actatgtaaa actttcttac attgtcatca gtagctggct tatctattat 53820 cacctctggc agaagctgtc caactggcga tgtgggaact gagggtccac caaccaagga 53880 aaccacacca ttgcaatcca ccgtgctgtg catcttccca ttggctggaa acaccgccag 53940 cattcgggag gacctgctgg tctggctcag gttactgttg cgtcgctctc cgtgtcttcg 54000 gggaacgaac agtgagtctc tacggctctc attatcctca aaggtgctgt gttcatcatc 54060 agcaaagtca ttctcagacc ccacatcctt ggctcgccct ctaaagctga aaagacttgt 54120 tctgctattg cgtcttgggg agaacaggga accacgaatg cttaacagag actgaaagtt 54180 tgaaacacat gacaaaaagt aaaattacat tagaactgcc tgttgaaata gttttgcaag 54240 tttaagttga agaatattgc attgttattt tagagagggt agcacattcc ttctgattaa 54300 tataatttat tggcattcag atgagattaa attagttcta tacagtatgg cttccagcca 54360 ttgatattaa ataacagata gctggagtgc agcctaaaag taatgggaga aaaaaaaata 54420 cccagccacc acgtctcaaa tttaaacaga gacatcctta aaaatctctc tatgtatgta 54480 tccacctaca atgaacatgg gcagcaagac agcaacggtt tttaatttct ctctcctttt 54540 ggataattcc aacaatagtt ttcacagact attttagttc agtttcctaa aaccatgtta 54600 tttatttttt tgacacagct gtaaaacaga ttacttgtag aaccagaaag taaaaatttc 54660 gaaattctga atgatgcact tttctataaa gtttatcatg gctaatattt ttaaagttca 54720 tgggataatt gataaagaag ttatgggatg acaaccaaca tggtgcctta aattaaccaa 54780 aggtacattt ctgagtagct aacccctagt ctacattttg ttgatgtggt tagaatagct 54840 gcaagattaa atgtcattac aattaccaga aggcacattt aacatgaaaa gccagttctc 54900 ctgtcttcca atcctgtgtt atttcaaaag cacctaagag tggatttgca tatatgtgga 54960 tgggaagtaa aactttcaca taactacata gaggggaaaa aacagtttta agtgtaatgc 55020 aacagtagtc aattcggttg atgaaaaccc atccatctat ttaaattctc tctcagatgg 55080 ctcactctca tcggtgtatc caagaactct gcagtgcgta cctgatgcgg ggaagagtac 55140 ctcttttcat atgtcagtct attcccttct atggagaagc gaaacccctt cctcctgatg 55200 ctgtcttcag actcagactt gtggaattca tcatcatctt tctcttctcc tccagactgc 55260 tctttctgtt tccttttttt cctccgattt cgtctttctt tagcactctt cgaactcaac 55320 ttagaggctt ctgaagagct atctgagagc ctgcctgctg cactgggctc cctggaatgt 55380 tctgaggctg ttgtagccgc tgcctgctat atagaggaga aaccaattca gtgtgttgca 55440 agaaacgact gcattaaatc tttaagatgc tcaagtttgg tgtgtcatgt ccaaaatgca 55500 agctaactga aaccaacatc tagatgatgt tttccaggta tgaagggaag tttttttttc 55560 tttttaacta ataatgaatt ttaaaaataa tctacttttc tccatggtaa catttattaa 55620 ctttgtctga tgccgcagag attcgtaaga ttcattggca gtcaagaata actcaagatt 55680 ctattcaaag ctggtaatga ggtagtgagc aggggtcctc tcaggtttcc atgcttatca 55740 aagtgttcaa tatcttccac atagtatcaa catatgtgga gatgttccac ataatcagcg 55800 ttatgaaaca tatcacagtt tcttcctcac tctcccctga tacagttatc tatagaaagg 55860 agagagttga gagctttctg ctaagcaagt taaaagatgt tcagttctct aaaagccatc 55920 ccaactatct tcatatcaat gttggctctt actagttatg gggtaagatg ctgtgtggtc 55980 acagcttgtt ctgttatgaa gaagttagaa cttcttagtc aacattcttc ccacaattcc 56040 cttaatctag aactgtagca gataaattag catgcttgaa gtaactcttt ttttttttta 56100 tggtcaagat ggttacaaat aaatttgatt taaatagttt aattagtctt tttgaaaata 56160 cacataatga attcgtatgt cccatttaga aaccacaagg aaacgtgggc aattggattc 56220 attttttttt ttttcattca gtgagtcagg tacactgaca agccatggaa aggtcaagta 56280 aacctcttgt agtactccat attgctaatg atgcttcttt gcctagtgga tggttttgac 56340 caagagaaca ttttattaaa aggaaattga acaaccccac ctaaagacat tgtatttctg 56400 aataaagaaa ataataaatt actttaatga aatggccaaa tgggttttat atgtcaacta 56460 atgaatttgc ttgtcagaaa agattgttgt cttatgatac tttttctaat gctagtatat 56520 ttgagtaaaa gattttaaac ttgggggggg gcaaaaaagc ccaaagttac tatttctctt 56580 ttcttcttga ttctatttaa agtgataaaa ataacataag aagcatcttc tgtagctagt 56640 gtaaaacagc tctgtacaac ttagtgatgt gactaggcca attcaaacta aaaagatgac 56700 ccatacatag aagtccttgg agtttgatgt gctcagcttt ctcacatcct gtcagatgac 56760 tctgcctttt gtttcattac agctctttgt aacatggcag tgaaagaggt gacaccagaa 56820 gactagagaa atgaaggtcg gagataagac ctacttgaac tgctgagtac ctgtgcagcc 56880 tcttgctgct tcttaagttg ctccaacatc tgctgaaatt ctgcctcttt ctgttcagcc 56940 tcctccagtg tggcctgatt ctgctcctca taggccatgg ccaccacagc caggatcaag 57000 tttatcaggt agaatgagcc caagaaaatg accagcacaa aaaatatcat gtaggttttg 57060 ccagcagcac gcaatgtcta gaaacaagaa tatgagaatt atttttacaa ttatgtcggt 57120 attgggtgac ttcacatttt aacttacttg tgtatgtggc agaactctga caaaattaac 57180 attgtgtccc atcagtattt ctttaacctc tatctcttct ttcttcttta agataagcat 57240 tcatagtcat aataagggat tcttggattc accaggaata acagttgata gaaagcaatg 57300 gggaccacca tgaaaaagct gagcctttca tggaaattaa agagaccaat ggaaaaggta 57360 atacttgagc agaggacagg gcagagggaa gacttggctt ttgcttagga gaaattgtat 57420 ctaagaggaa tgagaaatag aattcaaggc atggagaaac agaacagaat tactctcctt 57480 ggcgttactc catttaatgc gtattgtaat caatgggtta gaggagtccg agtcattctt 57540 tctctactgt atcatgctgc gggttgtgtt tcatgactca gtttgtgttc ttacacgctt 57600 ttacttaaat tttcagattc tcaccagttg gtatagattt tcccagaagt cctgagtcat 57660 cagtcgaaac agggacaaaa atgcccaact gaaggtatca aagcttgtgt aaccataatt 57720 agggtttcta ccagctttta cacacatata tccttctgga cattggctgc aaatggggaa 57780 aaagaaagta tgacaagaca ttctgctgtc ttcttactct ggtagaagcc tacacttaca 57840 aaataatcta gtcactactt aaaggacaca ggcgtgtgga atccgaattg ctgatacatt 57900 tcccaccttt gactccatag tatctatctt attagctgca aggtattgat attgcttagt 57960 aaccttttcc cctcactgtg aagtctccaa aggtgattca tagctttata cgtacaccaa 58020 gaaaatagca ttacagatca aagtgttgct tcttgcttta cagatgaaac tttaatattt 58080 agataatttc ttgttttatt tatatcatag ttactgacaa ttagtatgca taaagttagt 58140 tgctgttatc agtcaatttc tagagccaaa gatacacaca gacacatcca tatacaaaca 58200 tatgtatggg gacatactac acatacatct cacacgcgtg atcagcttac cctgcatcag 58260 agctatttcc acacagcagt gcatctaaaa caccctccag gaaataatga tatcctgttt 58320 gaaaaaaaga gaaagccaca tgatacacac ttgcattgtg aaacacatta aaagaagagt 58380 aggaaagtca ggtcttactt tttggttcac taagtgagtt tacaagtatc ttatcatcca 58440 cttaaacaca tgagtttttt ccttttcttc cttcaaattc tgttattaaa ttaaaggtat 58500 cgataatcaa ctgtacgagg tttttttctt ttcattatta gtggaatgtt agtgacaacc 58560 atgggtactt agggaacatt tatgaaaagg tatcagtatt ttctactact tttgtaaaat 58620 aaagaaaaag ttcatcatcc aaagaagatg acaatgatgg gtatctcaaa aataactaca 58680 tatttcaaaa gaaaaaaatg atatattttc ttgttctatt ttcatatttt caatccctgt 58740 taaaactttc aaattaatta taacttacat ttttcagttc gtagtatata tgtcaattga 58800 cacaaattgt atcaactatc tgaatatttt aatgaaatga aatattttag aattgaatat 58860 aaaacaaata atatttctta caaattaatg aaaaatgtag aacatcttaa atattaaagt 58920 taaaacaatt agagtaggcg aacatcaaat cttatcagtt ctccctagtt ctcaagagtt 58980 cacatctttc attactagag gagccatgtc tgcaagactt tccttggcca tccatttcct 59040 ttccatcaaa gattgacaag gaagaaacaa cctcaggttg tgtccagtag gttgtatgct 59100 cacacagtat cctcagaaaa accattatcc cattgcaact actcattcaa aaagtattag 59160 cgccgggcgt ggtggcgcac acctttaatc ccagcactcg ggaggcagag gcaggcggat 59220 ttctgagttc gaggccagcc tggtctacaa agtgagttcc aggacagcca gggctataca 59280 gagaaaccct gtctcgaaaa accaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaga 59340 aaaaaaagta ttagcagtat tagaaataaa gcgacgttca ttatccccct ataacttagt 59400 tgggattttg tatcctttca agaagtgaaa tgagtagata ggaacaacag aaaaaagaga 59460 atggaaacag gccacctcag gaggtaggag gtggggtgac cctctagaat gtaccagaga 59520 ccaggaaggt gagagacgct cagggggagg gaccttaggt gaaatgccca accgtgggta 59580 gaaggaactt gtagagccca cctccagtag aaagacagga catcaagtgg agggatgggg 59640 ttgccatccc aaagtcaaaa actctgaccc agaattgttc ctgtctaaaa gaactgcagg 59700 aactaaaatg gagaagagac tgagggaaag gacgtccagt gccagcctaa ttagggatcc 59760 agcccaaggg gagactccaa ggcctgatac tattactgat gatatggtgt gcttatggac 59820 aggagcctag catggctgca atctgagagc cccaacaagc agctgaaaga gtcagatgca 59880 gatacaccca accaatggac agaagccagg aactcctgca gttgaattag ggaaaggctg 59940 gaagaagctg aggaggatga ccaccccata ggaagaccag cagtctcaac taacctggat 60000 ccccgagacc tctcagacac tgagccacca accaggcagc atgtaccagc tgatatgagg 60060 cccctgacac atatacagca gaagactgcc aggtctgggt tcagtcagag aagataaact 60120 taacccttga gagacttgag atcccaggga gtggggaggt ttggtggggt ggggtgtggg 60180 cggggtgtag ggacatcctc ttggaaatgg ggtaggaggg aggaggtatg ggatgaggac 60240 tagtcagagg gcagactgga agtgggataa tgactgaaag attaaagtaa agaaagatta 60300 aagaataata aaagaaataa ggtgtgtaaa tattttcaaa atttacatca gataattttc 60360 taagtgacta caacatcctt gtgatcatgt ttagtctgtg actagacagg aagcaggcag 60420 actatgaaag gataagtaca catattgatg gttcttactt gagtcttgaa tgtatgattt 60480 ccagtcaaac tcgaacacgg tttcatttac aagtgtgcca ttgtaatcca tagttatatt 60540 cttctctatg ctatgttcct caagggaagc gttggtggga ggccactgta cacatttatt 60600 cctcaggttg cccatgaaga gctgcaaccc gatgagtgcg aacacactga gacagaacac 60660 agtgagtatc atgacgtcag acagcttctt caccgactgg atcagggccc ccacgatggt 60720 cttcaggcct gagagaaaga agtgtatcaa gcatctgaaa tattaaataa gtccttcaca 60780 caagtctctc ggagacacta aataaacgtg taagtcccaa aatgtggccc atggcaggga 60840 cattgtccta taaaaagttc gagagtgtag cttcatttaa gaacatagca ttcatgctgt 60900 tgtaggttat tctttaagtc ttataattgg tcttttgtta gcaaagaatg ggattgtttt 60960 tgcataggca tcaatgggta taatgaataa aaatgaaaaa tttatacata taatagggaa 61020 caaattcttt ataacattga cattacaaaa atactttttt tttctcgaga cagggtttct 61080 ctgtgtagcc ctggctgtct tgaaactcac tctgtagacc aggctggcct cgaactcaga 61140 aatccgcctg cctctgcctc ccaagtgctg gaattaaagg tgtataccac cactgtccgg 61200 cacaaaaata cattatatag taaaagttgg ttgggttgaa tatcagagtg tccacaaatt 61260 aaacacaaag gttgataaaa cctccagaga gagtaatctt ataggaagta ctcagtctta 61320 tgattctcag ctttctgtaa tgatgaatgg caagcaagga ggctcagttg aaaaagtctc 61380 agagttaact cactgattaa cctacatgct ttcatatagc tctcacctgg aatgactgaa 61440 atagttttca atgctcgaag aactctgaat gttctcaatg ctgagacatt gcccaggtcc 61500 acaaactccg tcacatatct gtaatgagga gttcacacac agacacaata acaggaagca 61560 aagaaagttt tgtaggtaca attaccttat gctttatagt aattgcttct aattagaaat 61620 gtgggaatgg tctttagact caatcctcta aatgtgtgaa tagctaaaaa ttacctaggt 61680 atacaaactt tgttacttac ctgtaaatga tttaagattg aaaagacact agcatttatc 61740 tgatatttta tgaagatctt tgctgctttt aaatagtgta agttgcaaat taaaatttag 61800 acttcatcaa tgtagtctta tttttcatga taaataccac aactaaatgt aaatttcata 61860 aaatatacaa tcttgatgcc atttggtagg caaggtagaa acactatatg tgaattggga 61920 aaattaacta aattaattag ttaactggaa ccaaatccac aggctagggt ttcagctaga 61980 aaagaaatga tataggaaat catccaacag aactatcgat tataaaagat tgcctcttgc 62040 cccactattc aagactcgca tttcctaaaa taacgtttga atagaagttg aacaaataaa 62100 ttaacaatag catcttacat ggcccaaggc cactctgtca tcacttctat tttagtctca 62160 agagtgagaa gtctcaaata ctgtcctgaa agttgtggct gaaacgcatg ggaacctttc 62220 atattccaat cagacataaa gttatacagt taaggtcaga catccaggat ttgcactttg 62280 gagccgatca gtaccatctc ctgtcctgtg tatcccttca ctcctgctga tgcccagaaa 62340 gtcagctacc cagatgggat aagtggtatt aatccactgt cctccatacc tacttttgac 62400 tattcttgaa tagctaccta ttattctcat ctcttcctgg tgtggagggg cgtgatttat 62460 cactagcaaa agggagaaga caggaaagta gggactgaat atacaactca gtgtatattg 62520 aaaagctttg tgttgagtaa aataaagaag agcctaaaaa caagagaggg agggagggag 62580 ggagggagag ggagggaggg agggagggag ggagggaggg agggagggag agagagagag 62640 agagagagcg agagagagag agagagagag agagagagag agagagagag agagagagag 62700 agagagagag aggaatacaa attgaatcag aagggaaata gaggcaaggt atgtctgctc 62760 aagaaataac catttatttg atttatgatg tatcaaatgt ctttttcacc ttaggatctt 62820 atttccagca tggctacaat ctttctacta ttctataaag gtaacaaaag aagccacggg 62880 gtgaggcaca acaggactat cagtgaaaag ttcagtgcaa gtttgtggga ccagtgcaaa 62940 ttttgctgtg tgaactttca aaaccatcct ccagctcagg agataaataa gttatgcttc 63000 agtattacaa gtatttgtgt gaggagacca gaatatacaa tattttcttt ctttttgggg 63060 ggtagggggt gagacaggat ttctctctat agccctggct gtcctggaac tcactctgta 63120 aagcaggctg accttgaact tagaaattca cctgcctctg tctcctgagt gctgggatta 63180 aaggtgttcg ccacacctgc ctggctacaa aattttctga tgttttaagt gttattaaaa 63240 ttgctattac tattctcatg gagcagtgga atgggtttac ccttttgagg taaatgttaa 63300 gacacggagt tcaggtgccc aaatcatgcc aggatgtttt accactcgag catgttgttt 63360 aaaaacctga gcatagacag caaaccaaac tgtattctct caggtttcca aaagagaagg 63420 cacttacgcg aatgtaatga cagtgaagtc cagccagttc catgggtcgc gaaggaaagt 63480 aaaatcttct aaacagaagc cccttgcaat aatttttatt agtgattcaa aagtatatat 63540 tcctgtgaag gtgtacctag aaacaagtag ccaaatcaat taaggacttt gtaatttcat 63600 tcagagtaca tcagcttctt agcatgttgt cctcggaaaa catggatacc aacaaaggaa 63660 acatgtgagt ttgaatagtt tcagaatcca tcacatacat agtttcttat ggtttttttt 63720 ttgtttgttt gttttgtttt gtttttttcc cagaatctga ccttccattt agaagcacta 63780 gaagaagagg ctttgggaaa cactgtgggg ggtgaaaggt cagaaaccag agagttctag 63840 gtgtcagaac atgggcaggc acgaaagctg cgattgaaac atccagagct ccagttacat 63900 aactgcctct ccttctactg gggcatcaag agctggccag tgtcattagt aatgcttcca 63960 gcccttgaga atgcttcctg aatttccact gtagacattt tagccttcca taaactgaat 64020 ttccaagttt tataatcctg aaactttagt taagttcttg atgatcatac ttaaaataga 64080 tataaacctg gataaatccc agtgatcaag agactcaata tggttcttta ttattattag 64140 atatttactt tatttacatt tcaaatgttg tccactttcc tgctttcccc tctgaaaatc 64200 ccctatcccc tcccctctcc ccctgctcac caacccagcc acaccctctt tcttgccctg 64260 gcattcccct acactgtggt tcttaatgta gcatttacag cttaatcatt ttgattctta 64320 attagcccaa ttaatgtgga ggttatctgg aataaaaagt ccagcatata ttgtctatat 64380 ttctgtagtt acttccatca attttctttt caaatactgg atcctgaaag aaaacccttg 64440 agttttctag tagactttgt atcaattata tgagtaaaga gaaatcctag atctgacacc 64500 agcaagcctg ggacccaatg actgctgtct tattttaaag ctgcatctat aaatggcttt 64560 atcacacatg ttctccagtt taatttaaag gctacattga gaaatagttt caaaaatctc 64620 aaatatatgt acaggaacaa acatttaaaa taaacttact ccacattctt tgtccagtcg 64680 ggagggttac tcattgtcat aaatacacag tttgtcaaaa tagtgcacat gattaacatg 64740 ctgaataatg taggttagtg ttaaggaaca tacaaaagaa agttcatgca ttgtattaaa 64800 aaaaaccaaa gtaacactga aaaacccaga cctcagttca acaggactca tgggtaaaca 64860 tgtgcacaaa tactacctaa tctccttaca tttcactcaa atttcatatg atgctaaata 64920 tgcatcatag tgtgacctcc acaatttcag agtaaatgag agtatggaag gacataagaa 64980 tacaagttgc tattgcggtt gtttttatac cagcatgatt accttccaag gtgctttttc 65040 taagcgggaa gtggaggtgg ttgggggggt ggtggatgca tttctctctt ttaaaatgta 65100 tttaaatttt atttgcaaca ttgttgagca gaaagcatgg atgtgaatta attgcacaat 65160 tagaatagta aattttcgag gaaggtgcat ttctgcaata ccgagatctc gtcgttaatg 65220 gatagaattt tgacgtcacg gtcaaagcag agcgtggtgc agagtgctaa gtagccgtgt 65280 tttgagtgag tttatgtaag cacaacagca tgagaagatg gaaggggaga tgtgtgaagg 65340 tcagggctca tcgccactgg gatgtaattg aaattccaca gtgacacctg ttcttgggcc 65400 aatcggtcac ttatcctttc tgtgccttca accaccctct ggctccacct acattcaaca 65460 cccggatgtt aagctggaca gactttgtta ttggtcgcgt agattaaagt aatcagtgag 65520 tatgaaatgc tcggaagcaa tgccgctgga gaaatgtgta cgcactgagt ggtaggtcag 65580 agaagaacag gtaatagggc cattgaaagt ggctgtaaaa agtgttttag aaatgccaga 65640 aataaccgct acgtcctgga gaaaacagat gatccgcagg atcttaaaat atgtgttttc 65700 tgtcttagta gcaggtattc tttctactac actcgactaa ccacacaaaa catttccatt 65760 aggtgtaggg aaagatttca tcaaatgacc acatgatggc actagaaatg caaactaaga 65820 tggaaaagct tttgagtgag cataggcact ttttataagg tacatcttta gtgttcgatg 65880 atagactatt aataggacta acgatttact tgtgatcaac tggactcaaa aagaagggcc 65940 tttatttttt gttgttgctt ttattgtttt tgttagttat tattttactt tcttgttttg 66000 ttttgtatct ccttttgttg gtgtagtgct gtttttttgt ttgtttgttt tatttttttt 66060 aaatgaacgt ttcttcttta gtcattgttt tttgtagtgc cagggaacaa atcaaaccca 66120 gagccttgtg tttggacaac tctttagatt ttagaatttg tgattttaaa aaaaatcttg 66180 ctagtatgac cttatgatac ttacaatagt atttttatac taattgtgac caaggccacc 66240 aaaagagact cagtcataaa tgaaggtttt tcactgatca atatccacgc cggaactgag 66300 ttgcagaaac ctttaaaccc aaaggcgacc acagaggcaa actcccttca accttttaga 66360 acagttttag cttctttcct gaatctgcac taaagagaca atgctataca acagacccat 66420 atattctgtg gcttaaatct gatattcagc caacttcata aaactgatca gaaaagttga 66480 ctaactagct aagcctgaag tgtcttgaga ttcttataag cttacatgat ccccccaaag 66540 gtctttaaaa tggcatacat catatctgtg tctaatctgt attttacttt gaaaatagtt 66600 tttttgtgtg tgattaattt tactgaaaat tttatgcaac tctgtacaaa gatgttgaca 66660 agaaacatgg cgatcttgca caaaacttag gggattcaat acatatatga aagctagtgt 66720 tagttgtcaa tctgacagaa tctagaatac tctaacagac gggcctcatt gcatgtctct 66780 ggggaattat tgtgactgct ttgttaattc agacggaaag acccatctac tgtggctggc 66840 accgttccct ggctgggatc ctggaatgta gactagggtt cagggctgaa ggggtgcctt 66900 aatggtaggg tgtttccctg acatttctga ggccccgggt tcaattctca gcactacaaa 66960 aacaaaaaga gatttccttg accaacaaaa gatattagat gaaagctata gagtatatgc 67020 acattttttt aacttaataa tacatagaag acacaatgaa tacaaacagt taacaccaac 67080 cacttgcaaa aggatatgag tgtaccaaaa tcttaatagc tattttccta agaggattga 67140 agggtgttaa aatgtacagg gcggaggtgg cactgaaccg gaagatggcc ttccctttat 67200 tcaatactat aaaagtctgt aaaataggaa taaacacata agtataaaac agacttccta 67260 ttttccaata gggttgcagt gaataattcc aattcagatg cccaggacaa tcacttttga 67320 tatgtaccat gagtacagct ctctctggtc acttatgtcc cagagatgaa cttacagtgg 67380 ctcttacctt ccaccaacca cttacctgag tttgtgcatc agccacgaga atgtcctcat 67440 ttccttaata ttttaagtgt cttacttaag ccaaagtttg aaatggggac acatttcatt 67500 ttcatcctaa cattcacaag aattccttct cataatgatt tgtttgccta gatgaagtat 67560 caggaaaatg aatcctgcag gatgcaaaat cattcaacag aaccgaatgt tttaaaaata 67620 aatattcctt cactacccgt gcttataaaa taaacatcat cgctccgctg gtaatagaga 67680 acaaaagcag cttccatcta gcccgcacct attggatgga tactatccag tcattgattt 67740 ctgcaggaca ggctccctgg agagtatctt gttgaccagg agtgctaaat tctgtattgg 67800 gattcctgag gtagctgaca cttggtttct aatcccaatt gactctcccc tgtgtggagg 67860 aaaagctcaa ggtccctgga gaactcagga cccataaata tgaagagcat ctacgacaag 67920 agtcagactt actacacagc aaagatcagt gtgcagaggg aaaagactca ccatgcaatg 67980 gagcaacacg gcttagtctg acacagtctt ctaagtcatt tactgatact cagcctaggc 68040 cgagatggat gaagctgaca tctctgtgaa taacacacta aatagagaga atgctaaggt 68100 ttgagtttat ttttttttta gtgactctat tctaattcct aagtatgggg aatgcaatta 68160 aggcctcctg catgctaagc aagtgtttta ccatagggtc atgttcccag ctcagggtgt 68220 gtgtgcacat gcgtgtataa tctataacca acccagagtg ttatacaagg gatccaccac 68280 cgaatgctgt ccccagcaca gcttttaata tgtttatgca tctattcctt aaaactccca 68340 tgttttagcc ttttgatgca tagctctatg gaccctgcta tgattagcac actctataac 68400 gtgccgtttg ttttctcctg agcatttttt gatagcattt cttcttcaca tttaaacttt 68460 aggtcactaa catgttttca ttttattttt cactttgacc ttgagatttt caaatggagc 68520 aatccttgaa cacagagttt ctgtttgaaa atagcccttt ctctctggga ttcaaacaga 68580 aaagctctaa atgtactatg aaaatatccc ctaagtagtg gggatctgtt agttttctca 68640 gctgtgacac acacacacac acacacacac acacagacaa aatccaacta ctgagagtaa 68700 aacctgtgtt tagaaagttg taatgcaatt ttgagtctgt tgaaaatgat gataaaataa 68760 aacaagagac tgtaggctgg gctatcccat ttcatttcag ttacttagca attaatgtca 68820 ctgtgtcata gataaacaga gaccacatca cctgggtggg aaaagtgctg cttctctaag 68880 cctgaccttt gaccacatgt catctaatca tcactgaatg ggtgcatcca gcacaaggga 68940 gacgacctta agatgtctgt gagggaggaa cgcactccag tggcaatcgc ttgtggttgg 69000 tacatagttc ccgttattct ctctgattca ttcaatattt ttgtccctaa acgaccttgt 69060 gaaagcatca taaaacatga atggacttgg gtaagggaaa tatccttgcc ttaaggaatg 69120 tgagcatcca aggacacaga acgagcaaag cttaggacca atgatttttt tcaaagttct 69180 tgcctgtacc tccttatcca gaaacacagc cagtcaaatg tgatagaaat attgggggct 69240 agagtaggaa ctgtagttaa aaaaattgta actagaaaga atatatactc ttcacctaag 69300 aatctaattt catatattac tatagaccga ttttgaaatg actatggtga tagagatgac 69360 aaacgagttt cagggttact gtagcatctt ttacaggctg gaggatgagt cttgggaggg 69420 tcagtagtag ttcagtgggc agggaaattc ccaggctcat cccattgaaa ctggctatac 69480 tcagaatcgc aatgacacag gttccttggc aaccttctgt ttacatgatg agtaaaggaa 69540 gctgtagtgg tttgaatgag aatagcccca gtaggcatgt gtatttcaat atgtgggcct 69600 cggatgtcaa aactgtttgg gaaggacttt gttggaggtc atgtgttaac agatgtaggt 69660 tttgaggttc caaaagtcca aaccaacctc agtttgtgtt ctctctgtct gtctctgtct 69720 ctgtctgact ctgtctctgt ctctgtctct gtctctgtct ctctctctct ctgtctctct 69780 ctgtctctct ctctctctct ctgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt 69840 gtgtgtctta ttcatggata cagtacaagc tctcagccac tgttccagca ccatgctggc 69900 ctgcctgcct gactgctgtc atactttccc ccatgatggt catggactca tgcgaacccc 69960 tacaataaat gctttccttt tcaggtttcc ttagtcatgg agttttgtta tggcagtagc 70020 aaagtcacca ctacaggaac acttgacaga aaatagaaaa gagaaaagag gaagcaggga 70080 caaaacagga attattagtg aggccaaagc tgagactctg aaacttagca agagagaacc 70140 aggagggaac tttaggcact ggaactcagc aaagcagtgt tggtaatagc tcggcaaccc 70200 cagtcctgat taataattga aaatttggac gaccagtggt tgaacacctt gacataattc 70260 ttaaattttc aaaggtttct gtcctttatg atatatttga tacatctatt tattaaatgc 70320 aaataatttg taaaaacatg ttgcataaag aacttcatgt gcaatgtagg tgggttgaaa 70380 caggagactg atgagctttg actgcacagc atgctttctg tactttaatt tttcataaga 70440 tttcttccca cccctgccaa ggactgtaac aatagtgcca gccttgcaga accactttca 70500 ttgtttctta cccaatgata gatatattcc ttttggattg aaacatacat gcaaatgcga 70560 gcttcctaca catcactctg aagtgtttat gggtttagct tcaatagctt tgcaatagag 70620 acagtattca gacttagata gcacctcatt atatgtagga ttgtagtcgt tatgaagtca 70680 ttaaatttga tttagaactt aagtttactt tttccaactg gtctgctatt tattttttta 70740 cccgatagta tctactatgt tcctcacaac tttactatag ttgagaagtc aggttacaac 70800 tgcagtgcca ctcagaaata ccgcactgaa ggcactgcat ggaggaaaga gaaaaggatc 70860 caaggggatc aatgttcact taaaacaaag gattaactcc aaagctacca accacccaga 70920 catccccctt ctctatttac atgtgcaaat tgcccagtgg caagcaccaa gagtgtacct 70980 tttagtagaa ggtactaaac cttctactaa acctatccct tgattcattt attatagggg 71040 ggggggggat aaatgcttta atctcattac tgcaatggag tagaaatata agcacttgat 71100 gagaacattt taataccaga ataattttct tccttggaac aagtttttaa acaaggcaca 71160 atgggtaaat tcagatataa cctttatgta taaaaactgg tttatagatg tatttatggg 71220 aactaagtat tcctacttag gccttaggac ttttccggcg tgtgtgtgtg tgtgtgtgtg 71280 tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgttaa aaaatgtctt tgtaatattt 71340 atatgacaaa aatgaagtca tatgctctaa tttaggtgta aaaggtgact gattagcact 71400 atatttgcaa agctttgtgc tgcattctga aaagaaaaca cacatatcta aatccgggca 71460 cttgcaaagg aatgctcagc tacagatagt agcacagatg aatctagaag acgaacatat 71520 ggaggtgtag atagcttaga actaaccaat aggaacataa tgtaaagaca aacctgtact 71580 ttaaccaagg atttctgatt gtctaagtac tacatgaaaa gccaaggaag aggtgaagtg 71640 cgtcttactg gtgttttctg taactcgaca acatttgagg ataacatcat attaaaaaaa 71700 tcactgaggt attttatgtg atttttttca caatgtctcc agtcttctca atctggtctt 71760 attctatttt aggtacccgt agccatacta gctgatgtct atctactgtg ctgaacagat 71820 ttgacctgac tttcaaccac tcattgacag accaagtcac actcttcagc aacccttgat 71880 ggaaaaatat tatttcaggt gttaaagaaa agcataaggt ggtttgattg aaaaccgata 71940 agcatccctg gtaatcaaca gttttaatga cccctcccct cctgccaaaa caaagaaaca 72000 aagaaacaaa gaaacaaaca aacaactcaa acctcaggga aaaataacag cagatttgtc 72060 tcaagttaag agcaagagtt ttgtgaagca acagttttgc tggttagcga ttaatcagta 72120 gtgattcgcc agttctcaat ggttatacag gatatgtgga ctgggccctt ctgcttgctg 72180 tgacctagta acttcataga acatgactgg ctgctgcgat tactgtcagg gatgaaactt 72240 ggatttgaca agtggtgtat ttgcactttt gttttctgaa tatacagcca ttggtggaaa 72300 ctttatttca atcaagagcc catttaaaaa aaaaaaaagt atacagttat aacttaagtt 72360 ctaattttgc atttcatcta gacattgcca gaaagctgtg acataacaga gattacattg 72420 aaatgtactc cattccctct ctaaaagtta gctacaggca aaagtcagag ataacatgtg 72480 aaagtgagct ggatgccagg catggtggcg cacgccttta atcccagtac ttgggtggca 72540 gaggcaggtg gatttctgag tttgaggcca gcctggtcta cagagtgagt tccaggacac 72600 ccaggcaccc agggctacac agagaaaccc tgtctcaaaa aaaaaaccaa aaaacaaaaa 72660 aacaaaaaca aaaacaaaaa gtgagctgga taactagaaa tattttaaaa gctgtacatc 72720 cagatgtgga gcctcactcc cgtaaagcta gcagcccaaa gctaaggcag gagtgttgtg 72780 agtttgaggc aagattgagt gctggaataa aaccttttct caaaagaaaa accaaataaa 72840 tagtaggtgt tataagcaga ctaaatatat tctttgcctg gaactttaaa tcacagggga 72900 tttttaattc acacatcatc tgccttctaa aaatgtatct ggcagtcaat tcctttggaa 72960 ttttaatgca gtttcacaga agagagtaaa taaatatgtt cttttttatt gttttttttt 73020 ttgtttgttt ggttggttgg ttttatttgt tttgtttttg ttttttgtct caaactcaat 73080 gtaactttct tccccaggtg ctgggatcca agccaggccc aacaagtgct aagtaagcac 73140 tcctccagtg aactattccc aggccttatg taattcctaa agaaatataa ttatgaatta 73200 atggtggttg gaactgtatc actatgtaga aggaagtgcc agtctggaaa tagtaacatg 73260 gctctaagtt gggctcaggt gcgcatctct actctgtaag actctggtgg tcagactgag 73320 aaactgccct aaccctatca gggagtgggg cacatttcca gaggttccgc agtaaggggc 73380 gggggtggga gggcagaatg agagtcatgt accaacatag cgatgcttca aagtctgatg 73440 cttcaggtag tcagagattc ctgtcagtct ccatctccgt gaacattttt cattcttgtc 73500 caatccatgc gtctaagtct ttttccctct ctgagaatct ttaaatggtc tcctttcctc 73560 ctcccctcct cttttatatt catggcttca aacaaagatt ttcctctttg gctcacgagg 73620 gatgacaagt ctcctcacag cttacctcac agcatttgct tctcggcagc aggctaacct 73680 caattaatct aacacagcct ccaccaagtt aatgggtaag gtctttaagc cactgattac 73740 aagctgaaat gaccagagag tggaaagagg gaatgggtat ctgagagtca ttattgtcac 73800 atttataaac tttgggagat aatttaaaag ttaaacagta ttgtgcaaaa atagcaaaaa 73860 ttatagatat cagtacttca caattaactt aagttttaac tttggatcta ctctcataca 73920 aaagagcgca ctgtatacag agggaagatt ctgtcacatc tatgttttct caggttggaa 73980 gagaaagcag ggcagatgga gggaatgcta tggcattatt tgaattgaca tttttttggg 74040 atctcctaaa tgatgccctt cactaactta aggccatcat atgatagaag atctattgta 74100 taccctgcaa ctagagaatc taacctcctc ctcatatgac aggccagatg ctctgttagc 74160 atcttctatg ttttcctttt tacagaagct tgtcttcgca tctaaattca gatgtcattt 74220 cctttcagaa gcccaccatt taagttttaa gtgtagttga attgtattag acgctgatac 74280 tgagcatgga agatttgttt ttacaaagca ggggtttggc aacatgccag tagcttactt 74340 attagttttt gcaatcttag acaaactatt taacctcagt tttattattc tgaagttgag 74400 accaaaactg tcttgaaaga acctgtaagg taccaacatg aatttaaaat gcaagtgcat 74460 aatatatagg gaggtagcag ttgttcattt ttacttatct ggaataactt ctctagaagt 74520 ttctatcttc taattgtgga gaacatctct gctccactgt ctgtccttgt ggcctaaata 74580 catttgcctc attctttagg acgtgattca gcatgtgacc cttacctggt ccagaattct 74640 tgctcagagt ttggaaaacg catgcaccta tcctcaaggt tactctgctg tagatgttaa 74700 cttactgtaa ctggggacta tttttgccat gtgtgggtga gcccacctat gcaggaagcc 74760 atcacagagc aaagcagagc ctacactgtc catgggctgt cctgatggtg tcagtttaga 74820 ttccacgtct tttgttattc aaactagact tggcccataa gtttgctttt cttcttcttc 74880 ttctccttct tctccttctt ctcctcctct tcctcctcct cctcctcctc cctcttcttc 74940 ttcttcttct tcttcttctt cttcttcttc ttcttcttct tcttcttctt cttcttcttc 75000 ttcttcttct tcttcttctt cttcttcttc ttcctcttct tcttctgtct ctccttcaaa 75060 gtagtttttg ctgagttttg gttactttta tccaaagggt ctcttaacta gtatgactag 75120 aataaactaa atgtcaaagg taatttattt gtcctgggac attttctgag gcagaggcta 75180 agggctgatt ttcctagaag aataaaacct tcctcaccct aactgaaaac aaaataagaa 75240 cttggtacct caatcataga cactcttgtg atgacagatg agatataaat tggaagcctc 75300 ttatgtgaac cccagtagag agatagtatc catcatttta ggtctgttgg tggagacaat 75360 aggttgtttt taatgttagg aaacattcaa ggacacagta cagtttttaa atgaatacat 75420 ttctatattc caaaatataa caagcttcta ttttcactgc agatctagaa tatctttcta 75480 tttctagtca aatgccacat tgtcaaaagg atatttcttc ccatggcact aatgagtcat 75540 ctgtaatttt aagaacataa gaggggagac gttttctgaa caaagagtgg gtgaagctga 75600 atgtataggc aaatggtaca gtagtagctc aagttatgaa accgacaaaa aaaaagtccc 75660 ataagaaaaa attgtactca caaactgaaa tgtccttgtt acacaaagtg aaggaacaaa 75720 tagaaagtat tcagcttcga ctcatacctt aaaggtcccc tgaggacagc aaccatgaga 75780 tggaaactca gtgcattgca actttgctat ctcctttcca cttcacggtt gttactgttt 75840 ctttcattgc taataaagga tctctgatca cagcttaaat cactttaata attttagtag 75900 aacatttgat tattacataa tttgcagatc agaaactggg tcaaagagga taaaaatatg 75960 tgggcatatg tcacgataac atataccact gtcagtgaca tttccactag cccaatggca 76020 ttggttatct ttataaaaag aacacagaga gccctggcat gctacagtgc cttcacacag 76080 cactctgcac atatggtgca cctgcacttt agcctgaggt ataccataaa gaatacattc 76140 tgtaaccatt gtcatggtca atgctattgt tcaatatttg cccttcccaa aactcataaa 76200 ttgaattatt ccataataca aggtgggaat atttaacagg ttattggtta atgaaggctt 76260 tgccttcaag aatgaattgg tgcctttcca gggtaagata atagaccctt cttgctcctc 76320 cttgccttaa acccttccac catgtgatgg tttagttcct caatcttgga ctctctggtc 76380 tccataagtt taagccaatc catttctttt cattataatt ccaaatgttg gatgtgatgt 76440 tacagcaggc taaagggtct tagagatttg gctttttaaa atcattttac atattgctaa 76500 taaatgagca tgatgattta tataaaaata actcattaaa taagttcaat ctaagggaag 76560 ccattgatgt ttgcatattt caactcaatc ttcaaaacaa atccatattc acagtttttt 76620 tcagtcatgg agaatctcac ccttaatgat ttttgaccag tagacccctt ggctgcttca 76680 actcattcac ttttcccctc ccttctaccc tccttccctc tatgtctccc attctctctc 76740 tctcattcat atatatatga aggctacata gtagtcacta aaacaaaatt agtgatcaaa 76800 tattagaaga aatattcttt taaaagactg agatttttac taagcaactt caatgtaaat 76860 cagagaaaac ttaatgttta tgaagattat accataagaa aacaatctat ttatgagaga 76920 aaatttaaga ccagtaacat aatatacagg caacctaaag aaggttttaa aacagagcac 76980 tatgaaagaa ggcaacattc tgaatgtggc ttggccatgt gttctaaagt actctatgct 77040 ggacaagctg acacattcct acaatccctg cacctgtaga aaggaggagt gtgagttcaa 77100 ggccagcctg ggatacatag ggaattgctg tctcaaaaac taaagaatga agcacatagc 77160 gtgtctgttt aaaaaacaaa caaaaaacaa acaaacaaac aaaaaaatct tagctctaga 77220 aatgtctacc tgcgctgcta tccagtggct cacatctgga gatctgtttg gtggaagaat 77280 aatgtgaaaa tgaaggacat gcctttcatt ggaaaaactc cttcctgata acaatatctc 77340 tcctatcagg ttgttctgct tgcacaatgt gatttgttcc aaaatgtctg aatgtttttc 77400 cttcttcaca caatgtgcat ttgaagataa ggacagctga tgtcaaaggc aggttggggg 77460 caggggtagg aaagctgatc tggctgccaa gtcatcagag ctgggcttac accttgagct 77520 ttttgtaaaa gctttaagta tttgtcactg ggttatgtga ttttgttttc cattttcctt 77580 tatgccattg tttttaaaat tttaaattca aaataaccca gtcagggacc atcatgggta 77640 gaaccacccc tcaaaacagt atctttcatc aatttaaaag ctctttgttt ttgaaaacat 77700 attcttttgc ttttattttt attatttgtt gattggttga ttgattttat tttatttttt 77760 taagacagag tcttactatt aactttggat ggcctggaac ttgctattta aatcaggcta 77820 gccttaaact cacagtgact ctcctccctc tgcctcctaa ttgctgggat taaaggtgtg 77880 tacaaccagg cctggtagtc tggaagctct ttaatttaaa agacaaaaaa aaaaaaaaaa 77940 aaaaaaaaag gatctgatag tttgatagtt tgtatggtga tttgagtaag aatggctctc 78000 ataaactgaa ataattgaat gctcagtaat caggggagtg gtattacttg agaaggatta 78060 gaaggtgtgg cttgacatag ttatggcttt gatggaggaa gggtgccatg gaagagggct 78120 ttgaggtttc caaagctcag gctaggccag gcccagtggt tctctcttcc tgctgcctgt 78180 aggtccagat ataaaactct tagctacttc ttcagcacca tgtctgcctg agtgctgcca 78240 tgctcccagc cataatgata atggtctaaa cctctgaatg tgagcaagct ccaaataaat 78300 gctttctttt tataagagtt gctgtggtca tggtgtcttt tcatagcaat ataacactat 78360 gacagtctgg ttaccacata gtgaattact atgcttttta aagtgtttcc atttggtctt 78420 ttattccttt atagatttat aaataaggac atcgtatagg ggctgggata ctggatttca 78480 attttgtatt ttgacagggc ctcctcttag taatttttat cattaataaa tcacttttat 78540 ttatctttgt ttctatataa ataaatagta actattaggt ggtggatttg gtctgtaaat 78600 tggaggtgcc atgtttgggg gagtaaatac ctgatgagga aaaggctttc taacctggac 78660 cataggagcc tctgaaacac tgcatgcccc cccgagaatt gtaagtaaat aaacacaatc 78720 catgagatga accaatttct atgtggaaca catctggatc tttattttgt aatttcctca 78780 tattcacttc tgacaaatag caattataga atgaacaatc tcctaaattg actactttta 78840 tgtcaccttg acataagcta cagtcatttt ggaaaaggga acctcagttg ggaaaatgcc 78900 ccttctctag attggcctgg aagcaagcct gaagtgcctt tacttgactg atgattgatg 78960 tggcatggcc tagcctgttg ttgtagtgcc acccccagga gggtggtccc aggtgctata 79020 aaaaaaatag gccaagcaag ccagtgagcg tgctcttccc ccgctcctgc ttcagttcct 79080 gattccaggt tcctgccttg attttctgcc ccagctttct tcataatgga ttgtgatgta 79140 gaacggtaag ctgaaataaa tcttccctac cttcaagttg tcttgggtgt ggatgtttta 79200 tcccaagaat agaaactcta actaagacat ttctctcacc ccaagctacc acatatggca 79260 gcttttgtcc tgacaggaac tgggctaaca gtacagtgtc cctaaaagtt tggagtattt 79320 taggattcgt ggtcaatgaa acacttgact tgcttggtta tatattcccc caactttaac 79380 aactggcaag tgtaattggc tagatagtgt cttcaaaaag ttcaagccag tatgaaactg 79440 tatcaatctt agaaacagag tctttgtaga cataatatgg ttatgatata tatgcatata 79500 tacatatacg tacatacata catatatgtg ctgaaatggt tgaattgcaa tatgccccca 79560 acaatcctat atatgtgaac tataagccaa aagaaatcat tttcccctaa aaacaagcaa 79620 caaaacaaca ataacacaaa atacccatgt atattgcata actgtattcc atgtggaaac 79680 gattacttag gaagttattt attatttata atatggcata gaaataaaaa cctcttgtgt 79740 tgtaaaactt ccttccatga gaaattcaca caatatattt ttaggtcttt ggtaactcag 79800 ggtgacttca acatttcaag gtacaaaaaa agtacttaaa attgcttagt ccttgtaatc 79860 ttcagtgaga gttttttttt aatttgttaa attagctgcc tacaaaatct tatacgtata 79920 tttagatttc tgtcatgggg catttggggc agctccatat ggtataatat aatttattta 79980 cttcttatga atatgcataa accacccacc aatctggtct catttcttaa gcagagggat 80040 tgttaagcct gtgctacttt agtatgtgag gtttctgtaa cagtccaatg taaatgtagt 80100 tagtggcaaa gtatacctga taaaaacact taccttctta ttgatatagt aggggtccag 80160 gtcctccaga ggctccgaca ccatctctgg aggaatgtct ccatagataa atggaaggtt 80220 cttcccagct tccaagtcac tgtttggctt tgggccattt tcatcatcat cttttttgtc 80280 tggcttggga ttcttagcct tctcttctgc aatgcgcctt tcaatagctg caagggattc 80340 tctggtgaag aagttgaagc tgtcaggtcc tggtggtaca agcactgttt gctccatctt 80400 gtcatcctgc acattttaat tactctttac tcttcatgtg agattcctaa ggagggaaga 80460 accagaaacg tggagaacat taaaagttat caatatcaat aaatactcat ctagaaaagt 80520 gggccagaag acttaaattt ttttctcctc caaaatttaa atggaaaaaa taaaaaaaat 80580 gtttacacaa attcattctc tatgttgagc tttggccaag cattcttgta tgtttaggat 80640 tgtgctttac caatagagga actaggctgt gagtttaaac actggttcag tattgctctg 80700 agtacatttt gataattgtc gccacatcac tgataaactg ttcactctga gatgtacctg 80760 tatgatgaag acgatgccca ctgatagatc aatcaattca aaggtatcac acacacacac 80820 acacacacac acacacacac acacacacac acacaaccaa aaaaaaaaaa aaaaccggaa 80880 ccttgtctct gagatctaaa atgcagccat tgaggcttaa caagtaagga caaagcagtt 80940 taactttgtt gcagtcaatc agaatcacat aaaaagacag tcattgctac actacttatg 81000 cctgtgtaca ccctgagatg tgggtgaata gatctatggc ctgagaacta cattagctct 81060 agtagagtct ctttgacaat gacaatccaa ggtgggacaa atgccattaa tatggctgag 81120 atggacataa actaaactgg aaaggaagct atgtgcacag gaggtagtag aaatgttctt 81180 agttcaagga acaatgtact tttcttcacc gaaacaattc tgatacatgg gagagtctgc 81240 agtcctgcag atattaaggc caaatccaag atgcatcctt ttaaaggtat acttaataag 81300 aactcaaatt tcacacatat atctgtgccc aaacttccca gagctcaagt tctgcctggt 81360 acagactctg ttttaatagt ctgttagctc attaaagtca gcaagctcaa tacaattagt 81420 tgcagctttg atgtctaggt ctctaataga aaactacagc ttcctcttcc tctcctccca 81480 gtgttctccc tccccccatt cacctttcca tttcttctca gagaaagtga aacctcccat 81540 tgatatcaac cctcctcccc caaccttggc atattaagat gtataagact agacatatct 81600 tcttctattg acactagaca aagctgtcca attaggggga agggatccaa agtcaaccaa 81660 tagagtctga gagagcccct gctcttgctg atagagatct cacatgagga ccaagctgtt 81720 aagctcttac atatgaatag cgggtcatcc catgcatgat gtcttgttgg tggttcagta 81780 tctgtgagtt gctatgcgac caggttagtt gattctgtag gatctcttgt gttctggatc 81840 tccctggctc ttcctctccc tctttgacaa gattccaagg tttacctaat gtttggctgt 81900 gggattctgc atgtattttc attagctgct gcatgaagcc actcaaatga atgttatgct 81960 agcctcctgt ctgcaagaac agcagtatgt aattaatagt gccagaggtg ggctccctct 82020 caatgcaatg gaatcactgt attttatctc actcattcat tcagatcatc ctgtctaggt 82080 atccctctca cctacttgat ggttttgagt ctaaatgtgc attgaattct atcttagtgt 82140 gtttatttgt tcttctcctt ttttttctct tattctataa accctatctt ttggtttgtt 82200 tatgactgtt gagtttggat ctcagcatgc accaaaggtg gagtggaact tgctccatgg 82260 ctcatactgg ctttgaaatt gcaattatca tgttatactt tcctaattgt ttggattgtg 82320 gtcttgcacc accatctctg attttattct atcaattcta gtgctgattc tacttatttg 82380 atgtgtagat aatacttatg atctgatatt tggaagtgaa ctgaactatt tacagcctta 82440 tgtcacttaa aagcatgagt atatattgag aaaaaaatca gtagatgatt ttaatgtgga 82500 aacataatag aatacttaaa tggacttacg tagtatagac aaatcactca acattaatgc 82560 atcaaagagt ccaatattca cgagacgtat gaagctgcta tcagcacagt gtggcctgct 82620 cttttattac cttaaacatc tttattagta gaaatatact ctaaaatatg attaaaaaga 82680 atattataga aaatccacaa actcttgaca gagctgctgt tatcatcatc gagtgttatg 82740 atacaagcat aattgaaagg ctgccatgat ctatgggact ggcagcagaa gatgtctgtg 82800 gatgccacca ttacctcaca tgtcctgtgt tgtgccatga gtttaggatg gatacatgaa 82860 taagtattgg gacttctaag ctccactcat ggagccagct ttgagttgca atctgtctgt 82920 gaccaaggca ccagtgtgca gtgcttgata atcctgccga gcacatagat ctttgcttct 82980 ctctctctct ctctctctct ctctctctct ctctctctct ctctctctct ctctctctct 83040 gtctctctct ctctctctct ctctctttac tgagaacaaa cgtaaacaca tatataaggg 83100 catttgtttg tttgtttttt ctcgtttgta tttctttgct gtttcatagg tttagcatta 83160 tcttttgtat gcaaatattt aaattttgga ttgcagcata atttaaatac atactaattg 83220 catacaattt cagtctttct gaaagggtgc aacaacaggg tccatttttc ataaaattgt 83280 gtggacagaa cagaagtggc tacttcaagc cttcctattc agtaaaaatg agcaacccac 83340 aagacctaac agtattatgg tgtgcttaca gccaggagcc tagcatgtct accctcagag 83400 aggcccaaaa agcagctgac tgagacagaa gcagaaactt acacccaacc aattgtctga 83460 agtcagggac ccctgtggtt gaattaggaa aaggctggga gaagttgagg aggagggcga 83520 ccccatagga agaccagcag gctcaataag cctaggctct tgagatctct cagacactga 83580 gccaccaacc aggcagcata tactagctca tccaaggtcc tggacacatg tacaagtagg 83640 acttcctggt ctggcctcag tgagaaaaga gcccctagct cttgagagac ctggggctgc 83700 agggaatgga gagacctggc aggggtgttg gggggagtgt ggggtgtgga gaccccttag 83760 agatgggggt gggagggtgg ggaggagaaa tgggatgagg aactgtctga gggcagaatg 83820 ggagggggat aacaacttga ctataaaaga aaaatattaa atataattaa atataaataa 83880 aaagcagtat aagaaaaaat gaaaaaaaaa aaaaacctta gggctattgg ctgtcagtat 83940 caactgagta aacaaacagc caaaaagata ggcaaatact actgatgaat atgaccactt 84000 caaatttatt gttataataa tgacctggtt cagttacagt aattacactc atatgtgagt 84060 aatttaacta aatactatac tgataacata ttcaggttag ggggaaagta tttcttactt 84120 tctgattaga ccttgtattc aaatactacc aaaaagtaaa acataagtta tattaattat 84180 aagaataata ccatttcaag attgtgatct ggggctaaag agatggcttt gctaaaggtg 84240 cctgttcatg cctggtgacc ttgagcttgc tgtctgcccc acagggtgga tggagatgac 84300 tgattcctgt gagttctcct ctaagctcca ccatgccact tttccatctc cctccctctc 84360 tctgtctctc tctgtctctc tctcttaaac aaacacacag gtacacacac gcacacacag 84420 atactagcta agtaaacaaa taactgtaat tttaagcatg atgacctgtt ccataaggtt 84480 gcttatgaaa tatctgaagc tgtcaaatat ccttcaatat taatgttttc aagcaatatt 84540 atgggcaaaa atctatagat tttagtttga acttctactt tctctatcca gaaataacca 84600 ttaggataga aagaaaaagt ttggattttt aacttaaaat ttttaaacat ttaaactgaa 84660 aactgagaat ggtccccatt tgtggaaaca catgcctcat tagagatgtc tcatttgagg 84720 accatgtggc ttgaggcttg tggcggtctc tttactttag tgtgactttg gatgccttgg 84780 ttacatagag cagcccgtgt acccttcagt agagatagcc aacaaatcgt ggtaagaaaa 84840 gtgtcaaaga gagagtaata ttttaaagaa aaatataaga taagaactta ttcaaaatgc 84900 aaactcacat agttatgaag aaagaaaaat gatgcatttc attaacagac atacttaaaa 84960 taataaaaag aagtaaattg ccaagaaaaa aatgaattat tcttttagaa aatactttta 85020 aaaattaaat atagacaagt cattcgaaag aaggcaacaa gaaacagtaa aatctcctaa 85080 agacactgga atagaagtga ggacctgagg gctggaggga tggctcagag gttaagcgca 85140 ctgactgttc ttctagaggg tctgagttca attcccagca accacatagt gtcttataac 85200 ctctgtaatg ggaactggtg tgtctgaagt gaataccaca tatgtactca catacataaa 85260 atgagtaaat cttttgaaaa aaataagtga ggaaaacatt taaaactaat aaaaatttaa 85320 ttcacaatgg gaaaaacagg gatgaaagag aaataagaat gaattacttc attcaaatag 85380 gaaccttctg gctttatcgt caccaacaat tcatacttta tcgtcaccaa caattcatac 85440 tttatttcta taacttttaa atgtttttct aaacctggta atcccagcta tcagttaata 85500 tggttattca atatcagtac atcttagcta tattatgcca cataatttta tgtgtgaagc 85560 aatgctatat gtgtagtgtc ttctaaaata gcatggtatt tatagtgaaa attagctgga 85620 ttcttgctaa catgatggtc agctcctgca agccttacca ctattttgag gacatcagtc 85680 ctctagatag cacccttctt aattaaattt ttggtctact ttgcaaaata ttctactgcc 85740 aaaaattaaa gtcaggtgaa atattattct tattgatatt atctcacaaa aataactaaa 85800 atatttatta gtgtgtgtgt atgtgtgtgt gtgtgtgcct gtgtgtgcac aagtgcatta 85860 agtgtgtata tggagacttg tgcggggcat aaaactggag gtcagagagc aactttgaag 85920 agctgcttct ttctttgtaa ttttatgtaa attcctagga ttaaactcta gtcaacaagt 85980 gtctttgccc actgagccat ctccctgatc acttaaccac tgactaattc tataaggctt 86040 gcattgtact tagtgcattc tttgttcttg aatcaaaaac caaaaccaaa gggacacaaa 86100 ttgaaaagga agatgtcaaa atatcactat ttgcagatga tatgatcgta tagttaagtg 86160 atccctaaaa ttctaccaga gatctcctaa acccgataaa caacttcaac aaagtggctg 86220 gattataaaa ttaactcaaa caaatcagta gccttcctct actcaaagga taaacaggct 86280 gagaaagaaa ttagggaaac gacacccttc acaatagtta caagtaatat aaaatatgtt 86340 ggtgtgacac taaccaagca agtgaaagat ctgtatggca aaactttaaa tccctgaaga 86400 aagaaattga agaagatgga aaaatctttc atgctcatga ttggcaacat taatttagta 86460 acaagggaca tcttgctgaa agcagtctac agactcaatg gaatccccat aaaattccca 86520 ctcaattctt catagagtta gagcaatttc aaatgcattt ggaataacca aaaacccaga 86580 ataatgaaaa ttattctcga caataaaaga acttctgggg ggaatcacca tccctgatct 86640 caagctgtac tgcagagcaa ttgtgattta aaactgcata gtaatggtac agtgatgggc 86700 aggaagatca atggaataga attgaagatc cagaaatgaa acccacctac ctatggttac 86760 ttgatctttg acaaaggagc taaaaccatc caatggaaaa aagcattttc aacaaatggt 86820 gctggttcaa ctggcagtaa gcatgtagaa gaatacacat tgatctgttc ttatctcctt 86880 gtacaaaaca caagtccaag tggaccaagg acttccattt aaaacaagat acactaaagt 86940 taatagaaga gaaagtgggg aagagccttg aacacatgga cacaggggaa attttcttaa 87000 acagaacatc aatggcttat gctctaagat caacaattga caaatgatat ctcataaaat 87060 cgcaaaactt ctctaaggca aaggacactg ttaataggac aaaaggcaac caacaaattg 87120 ggaaaagatc tttactaatc ctaaatccaa tagagggctg ttatctaata catacaaaga 87180 actcaagaag ttagactccc tttactacag agcaattgtg ataaaaacag catggtactg 87240 gtatagagac agacaagtag accaatggaa tagaattgaa gacccagaaa tgaacccaca 87300 cacctatggt cacttgatct tcgacaaggg agctaaaacc atccagtgga agaaagacag 87360 cattttcaac aattggtgct ggcacaactg gttgttatcg tgtagaagaa tgcgaatcga 87420 tccatactta tctccttgta ctaaggtcaa atctaagtgg atcaaggaac ttcacataaa 87480 accagagaca ctgaaactta tagaggagaa agtggggaaa agccttgaag atatgggcac 87540 aggggaaaaa ttcctgaaca gaacagcaat ggcttgtgct gtaagatcga gaattgacaa 87600 atgggaccta atgaaactcc aaagtttctg caaggcaaaa gacaccgtca ataagacaaa 87660 aagaccacca acagattggg aaaggatctt tacctatcct aaatcagata ggggactaat 87720 atccaacata tataaagaac tcaagaaggt ggacttcaga aaatcaaata accccattaa 87780 aaaatggggc tcagaactga acaaagaatt ctcacctgag gaataccgaa tggcagagaa 87840 gcacctgaaa aaatgttcaa catctttaat catcagggaa atgcaaatca aaacaaccct 87900 gagattccac ctcacaccag tcagaatggc taagatcaaa aattcaggtg acagcagatg 87960 ctggcgtgga tgtggagaaa gaggaacact cctccattgt tggtgggatt gcaggcttgt 88020 acaaccactc tggaaatcag tctggcggtt cctcagaaaa ttggacatag tactactgga 88080 ggatccagca atacctctcc tgggcatata tccagaagat gccccaactg gtaagaagga 88140 cacatgctcc actatgttca tagcagcctt atttataata gccagaagct ggaaagaacc 88200 cagatgcccc tcaacagagg aatggataca gaaaatgtgg tacatctaca caatggagta 88260 ctactcagct attaaaaaga atgaatttat gaaattccta gccaaatgga tggacctgga 88320 gggcatcatc ctgagtgagg taacacattc acaaaggaac tcacacaata tgtactcact 88380 gataagtgga tattagcccc aaacctagga tacccaagat ataagataca atttgctaaa 88440 cacatgaaac tcaagaagaa tgaagactga agtgtggaca ctatgcccct ccttagaatt 88500 gggaacaaaa cacacatgga aggagttaca aagacaaagt ttggagctga gatgaaagga 88560 tggaccatgt agagactgcc atatccaggg atccacccca taatcagcat ccaaacgcta 88620 acaccattgc atatactagc aagattttat cgaaaggacc cagatgtagc tgtctcttgt 88680 gagactatgc cggggcctag caaacacaga agtggatgct catagtcagc taatggatgg 88740 atcacagggc tcccaatgga ggagctagag aaagtatcca aggagctaaa aggatctgca 88800 accctatagg tggaacaaca ttatgaacta accagtaccc cggagctctt gactctagct 88860 gcatatgtat caaaagatgg cctagtcggc catcactgga aagaaaggcc cattggacac 88920 gcaaacttta tatgccccag tacaggggaa cgccagggcc aaaaaggggg agtgggtggg 88980 taggggagtg ggggtgggtg ggtatggggg acttttggta tagcattgga aatgtaaatg 89040 aggtaaatac ctaataaaaa tggaaaaaaa aaagaaagct cagcactaca aaaaaaaaaa 89100 aaaaaaaaaa aaaaaaaaga agttagactc cagagaacca aataacccta ttaaaaatcg 89160 ggtacagagc taaagaattc tcaactgagg aatcccaaat ggtagagaag cacctaaaga 89220 aatgttcaat ccgggcgtgg agaagcacgc ctttaatccc agcacctggg aggcagaggc 89280 aggcagattt ctgaggtcaa ggccagcctg gtctacagag tgagttccag gacagccagg 89340 gtgatacaga gaaaccctgt cccaaaaaac caaaaggaaa aagaaaagaa aagaaaagaa 89400 aagagaagag aagagaagag aagagaagag aagagaagaa aagaaaagaa aagaaaagaa 89460 aagaaaagaa atgttcagca ttcttagtca tcagggaaat gcaaatcaaa acaaccctga 89520 gattccacct cacaccagtg agaatggcta agaccaaaaa ctcaggttac agcagatgct 89580 ggtgaggatg tggagaaaga ggaacactct ttcattgctg gtgggattgc aagctggtaa 89640 aaccactctg gaaatcagtc tgttggttcc tcagaaaatt ggacataaga ctacctgagg 89700 acccagctat accactcctg ggcatatacc caaaagatac tacaacatat aacaaagaca 89760 catgttccac tatgtttata gcagccttac ttataatagc cagaagctgg aaagaaccca 89820 gatgtccctc aacagatgaa tggaaaattg gtacatttac acaatggagt actactcagc 89880 aattaaaaac aatgacttga tgaaattctt aggcaaatga atggatctgg aggatatcat 89940 cctaagtgag gtaacccagc tacaaaagaa ccacaaggta tgcactcact ggtaagtgga 90000 tattagacca aaagttccca atacccaaga tacaattcac agatcacatg aagttcaaga 90060 agaaggaaga tgaaagtgtg aatgcttcag tacttcttag aagggggaac aaaatattca 90120 tgggaggtag agggtagggg tgacttggga ggaagagagg aagaggaggg ggaaagggag 90180 gcaggattag ttatgagagg agatggggat gatatacaga ggggcaggaa tttgaacaga 90240 ggtgtgtagc aatgggggat agggaattgg ggatatccat cagcaagtcc cagatgccag 90300 caaagattgg ggggaatgag accacccact catctcaaaa ttcttaaccc aaaagggttt 90360 tcttgtctaa aggaaatacg gggacaaagt gtggagcaga gactgaagga aaggctatcc 90420 agagactgcc tcacctgggg acccaaccca tagacagaca ctaaacccaa acactattgt 90480 agatgctaag aagtacttgc tgacagaagc ctgttatagc tgtcccctga gaggctctgc 90540 cagagcctga caaatacaga agatgcttgc agccaaccat tggacttagc acagggtctc 90600 tgacgtagga gttggagaaa ggactgaagg agctgaaggg gcttgcaacc ccatagggag 90660 aacaacaata tcaatcaacc agacctccct gccccagagc tcccaggaac taaaccacca 90720 accaaagagt atacttggag aggtccatgg ctctagctgc atatgtagca gaggatggca 90780 ctgtctggta tcaataggag gagaagccct tgatcctgtg aaggcttgat tttccagtgt 90840 aggggaatgc cagatcaata aggtggtagt gggaacattc taatagaagc ggagggagta 90900 gggatgggag aggaaaccag aaaaggggat aacatttgaa aagtaaatac ataaaaatcc 90960 aataaaaaag tagacaacaa actaaaacaa caacatcaaa agaaagaaag gaagaaagaa 91020 agaaggaaag aaagaaagaa agaaagaaag aaagaaagaa agaagaaaaa agaaaagaaa 91080 gagaacaaaa tttttttttt ttaggtcagg atctcttttc ctaaccctga ctgtcctgga 91140 attcattgtc cagatcaggc tggccttgaa ttcacagtgg ccttcctttg cctcctgagt 91200 gctgagatta aaggtgtgca ccatcatacc catcctcaaa agctattttg acagaataaa 91260 gtgctgatat gttctcagat caagagccta aaaaccatta ggaaattctt tatatactat 91320 caatttttga gaaatataca tttgtataag ctctgttttt atttgtggat gtatatatgt 91380 attttttctg tgttatttct attatgtagt ctttacttgc ttgaagtttc agtttaatga 91440 taaatgccct cttctctctt gaaagtgtct taaatgtatc tcaaatatga tgccaaatat 91500 tctggtgtag gggagagaat gatatggatg agcagtgaga gtctttaggt tggtaaggag 91560 attgcagggt cataaacagg atgacacagt ctaacagggc aatacaccca gatgaaaggt 91620 gtagcccaga ttaaaggtgt gttccttaaa ctcggagatt caatcttctg gaatccattg 91680 ccactatggc tcaagatctt caaaccaaga tccagataag gatctccaag cctccaaata 91740 agggtcactg gtgagccttc caattccgga ttgtagttca ttccaaatat tgtcaagttg 91800 acaaccagga atagccacta caatccaccc cttgtcaact tgacacaaat aatatctcat 91860 gttcacatga aacaataaca aggttgtaaa tatgcctaac atgatataac tatctctcgt 91920 acaatcgcaa atgcattagt aaatttacaa tgggcattca ctaaaaagac agagaggcca 91980 agacgggttt gatgaggtga agtggcactt cttgatattc agtcggggct gatacccaaa 92040 tatccactta gttggaggag aattattcac ctgggtgttt aacctgcagg cctccccaac 92100 cagtggaaat cctgctatgc tcttcttgcc cttgtataat tttgagtaat agacttttgt 92160 gctgatggaa tgagacttat aaactctagt caagctttct ctgaagcact gtgtgtctac 92220 atagcctcat gctctaggtc ctttgctctg agaatggtat atctcaaatg ggtgcttctt 92280 cctcagtctg gatcctggaa taagaagaca cattcactgg atgtcaagag aaagctaata 92340 ggactcaaag ggtctaaaag taacgattta tcagtgatgt ttgacagtga tattactaac 92400 gagcaagtgt atgccattga tcaaagacca ggctgctaaa tgagttgaat taattaggaa 92460 tatttgtctc tcagacacaa atgttgccag agattagata ttccacacct catgagtctc 92520 cacctatagt tctagatgag gaacacatta tcattaggca atcagtgaaa tcatggcctt 92580 ctaacaatca tatagcaact caggaaaatt tgttcaaagg atgctaaata gcctatatca 92640 agaatacaaa gagtgggctg gggagtagtt cattagtaaa gcagttgcca tgtaagcatg 92700 gatatctatg ttcagatctt cagtacccat tgaaaaagct gcagcatcat ccaatgccta 92760 gaattccagt gctggaggag cagagacagg ggcatcatgt gggcctactg ccctgacagt 92820 ccagctgaat caagaatttt aggttcagtg agagatcatg tcacaaaaac taaggtagaa 92880 agcaacagag aaagaagtgt gatatttatc tctggtctct ctatgcacaa gaacacacac 92940 acatgctcat acacaaacac tccacactcc tgggtatata catgtctaca ctcatgagca 93000 catacatgca taggcacaag cacacactcc caaacaggga tacatacaaa aacacacaac 93060 aaagaatatg tattatcaat cagaagccaa ttatttaagt taagtagtaa aaaattcttc 93120 tactaaaaag acaaccgtac catggtgagg aaatggtcca gtcaatgata tttgctagaa 93180 ctgtcattgt ccatccatgt gtctatgctg cagcatttaa gatatcaaga aggagctggc 93240 ctagtgagaa cagaaaatct aacatggctg ctatagctta ctgactagaa gttaagtgca 93300 cacttcctaa aagaaggctt tgacacaagc cacttcagtt ccctcctcat tttcttgtcc 93360 ccattcctct ctctgtagaa ttctgagatt tcaattcagt tttatacaga aaccacatta 93420 ctgtaagccc tacaaagtta tggcaatata gctatatgga gtcaagtaat gtaggttatt 93480 tttttcccaa tggtgctggt gaaggtggca attatgtagc tatacttagc agactgagga 93540 aattctgcta gagtcagcat ttgtctcttc attgctatga aacagtaatg gaaaaataaa 93600 caaaaacaaa aggcaaacac tatgcataat tccctcagat catattaaca tgtgatgttg 93660 gagtaaattg ttataacccc attttggaaa tacttacctt aattaactat gatttcctta 93720 aaataatgca gtatttacaa tctatatgaa agcactatat gggacacatg gtatgatgga 93780 acagtgcacc caagagacac caagaacatt cctgtctgtg gcagtctttt ctctatacag 93840 aggcatttag tctcaattgc tcagagttat tttacgtttt cagtgacttt cactgttcat 93900 tcgtgtgcat attgcctgga caacacagga tgaaaaatgg tccaagagaa gtctttgact 93960 tgctaaagca agaaagatgt ttaaaatatg cgacacatga aatatcccaa aaagtgtaga 94020 attctttttg agaatgttga tgtctcttta gcataaagct aatttgaagg tgtccttctt 94080 atcctaatat tttcttacaa aaccagctca tctcaaagca aaagtgttca agatatagtt 94140 gatggagtaa ggagtttagc acacagaaca cagggacagc tacagagaaa cagcaaatag 94200 ccaaggcaga cataaagagg ctgacaagac atgagagaga agagtattaa acacagatca 94260 gctacctgga aaatggctct ctggtgttcc acacttcctc tcatctggat gatctagaaa 94320 cacagtaact gctctgagtt aagaaagcct gagaccagca gtgtgtgggt ggcctgcatt 94380 aagttgattg ataaacattc tacatataaa atctgtaccc ttcacaagtt tggtcaatga 94440 cacaattcta ttgtaatacc atagactcat gttcaaagaa gaatcattta aggacagagt 94500 gtgctgaaag aatgtatagg aaataagtca caaaagatga cataatttct tgatttaaaa 94560 cctcacagga tcataggatc agaggtgagg aggacacaac atctgtcaaa acacaggaat 94620 taactaggac caatgggacc caggcacaca ggaactccac cagatcagtg gcacaagttc 94680 cttctggtct gtctgggtca gtgccctgag cagaccttgg gcttgaactt cacagccagt 94740 cccacaacac ccagaggaag ctccactccc aagtgctcta acatgccgag gatcacagga 94800 tcacagaagc ttggtcacac caggatctca gggtcccaga ggcagcttaa ctcccaggag 94860 ctctgaccca ttcaggatcc cagaaccaca ggatcacaga gacagcttga ttctgaggag 94920 ttctgacaca accagtatca caggaaggat gagctccagt cagatatagc cagatatatc 94980 aggtagcact agagataatc agatggtggg aggcaagcat aagaacataa gcaacagaaa 95040 ccaaatttac ttggcatcat cagaacccaa ttctcccacc atagcaagtt tggatacacc 95100 atcacaccgg aaaagcaaga ttcagaccta aaatcacttc tcatgatgat gatagaagac 95160 tttaagaagg acataaataa ctcacttaaa gaaatacagt taagcaggta gaagtccgta 95220 aagaggaaac acaaaaatcc cttaaagaat tacaggaaaa cacaattgaa caggtgaaag 95280 aaacaaacaa accctccagg atctaaaaac aataaagaaa tcacaaaggg agacagctct 95340 ggagattgaa aacctaggaa agagataagg agtcatagat gcaagcatca ccaactgaat 95400 acaagagata gaagagagaa tctcaggtgc agaagatacc atagaaaaca ttgacacaac 95460 aatcaaagaa aagacaaaaa gcaaaaagct aatccaaaac atccaggaaa tcaaggacac 95520 aatgagaaga ccaaatttaa ggataatagg tatagcagag agtgacgtgt tccaacttaa 95580 agagccagta aatatcttca acaaaattat agaagaaaaa ttccctaaag aaagagatgc 95640 ccacaaacat acaagaagcc tacagaactc caaatagact ggaccagaaa agaatttcct 95700 ccagtcacat aatcaaaaca ccaaatgcac taaacaaaga aagaatttta aaagcagtaa 95760 gggaaaaagg tcaagtaaca tataaaggca gagctatcag aattacagaa gtcttctcac 95820 cagagactat gaaagctaga agatcctggg cagatgtcat tcagactcta agagaacaca 95880 aatgtcaacc caggctacta tacccagcaa aactctcaat taccatagat gaagaaacga 95940 agatattcca tgacaaaacc aaatttacac aatacctttc cacaaatcca gccctagaaa 96000 agataataga tggaaaacac caacacaagg agtgaaacta caccctagaa aaagcaagaa 96060 agtaatcttt caacaaacgg acacaaacat aattccacct ttaacaacaa aaataacagg 96120 aattaacaat cacttttcct taatatctct taatatgaaa attaatatta ccaacatatc 96180 ttaatgaatt gaaattcaaa tatatgagga attagaaatt tgtcggctgt cttccagtgg 96240 tctctctaat ttggtaatgg gagaaatagg tccaatatta tacaatccat atacactttc 96300 tgcttgtttg tatatgacaa agtctagctg tgtaccacac aatggtcttg aaatcatgct 96360 tctcctatct cagcatatct atttgtagga ttgtttattt aatgttttta cactactcta 96420 tggttttcag aacagcttac atatttcaaa atcatgtata cagcccaaag aaatatagaa 96480 aattaatttg ggaggtagct tgtaagagaa caacaaagag tgagactgaa cttttttttg 96540 atatttataa ttattgtatc aattttgaag aagaggacct tataagttac tttttttctg 96600 atatgaatgt ttttcagaat tatcacagtc aaaggaacca gaatcttaca ctcacctaat 96660 gtctgtgcca ccctccaagc agagccattg ttcattgaaa caattgatga atgactccat 96720 ggatagacca tcttaataca caccatttct taaatgaatg taacctgctc cctgtaggct 96780 gagaatgatg acaatcactc aagtcaaata gttttgatta tagaaggaaa tatgtatcca 96840 aataatcgtg cctgcaattc attccttggt gcagcagaac tgtcaactct tagcttaact 96900 actatggagg taaaatcctt tggtgatgtg agggacattg aagtacagac taattacaat 96960 gaactccaat atctaaaaat tgttcttatt ttgggtttgt accacagtaa gagtcaagat 97020 tttaaagctc tactaaaaac aaaacaaaca agtaaacaaa atgactttat ttatgttcat 97080 ttaataacat gtcgatcatt ttatgattgg tataaaaata tatattgtgc tgaatatgat 97140 aaaaaattag ttcacttaaa aataaaataa agactcacta ttttaattgc ctctatgcag 97200 catttatcat atatgatatc aaattacatc taatttatta ttcaaaacta tactggttag 97260 ctttcaatct gacagttaaa gtcagtcaac cagtgtttct tttgtgatgt actggactga 97320 tttatagaga cccttctggg attcttagct ttctgtgtgg tcaccagcta atgactgtca 97380 gctctgtaca aaggacacac taccagatgc caggacatct gtcacagcag ctaggacaca 97440 gagccaaatc tattcttgtc ttgatgtatg acacacaata tgtacaatca gttttgttca 97500 ttttgaaagt attctttaat atatgctaca gacaagaccc tgcaggacag tgaagaccgt 97560 acggtggcag ggggagtgga aaataacata gtattgggat cttgagacta aagcaatttt 97620 cttcacaaga ttctttatga aatcagctct gagattttga tttgttttgg aattttgatg 97680 tttctgacct taatggagtg atgtattagt cccagaatag gtgaaaatga aggttaaaca 97740 tttttggcat caacttaaaa tacagaaaac ctcttttgac ttcttgagtc tgtttgtatg 97800 tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtctg tgtgtgtgtg 97860 tgtctgtgtc tgtctgtctg cctatgcatc tgtgaaaagg caaggagcag taacactatc 97920 ctgaattatt actaatttat ttaaaggtaa aagaataaac atcatgtaac ctctcttaat 97980 aaatctcaca taaagtggtt ttttttctaa caatagattc acattttaat tcttatttca 98040 attaaagaac ttttgatgca ttaagctcaa aaccataaac atgtcagata acagaacatt 98100 aagttcaagg aatatcctac actctttagt tctaactagt tttgaagtta tgttcctttt 98160 tctcatagat caaatggtga aaaactataa aatagtacta ttaatataca tatgagagat 98220 ttggtttctg aatctatgcc ttttctccta ctcagcatgt cttctaacat tttttggcta 98280 tttttttatt ggttatttta tttatttaca tttcaaatgt tatccccttt cctggtttcc 98340 cctcaggaaa cctccattct atcttctttc cccctgctgc tatgagggtg ctcacccacc 98400 cactcctgcc tcactgtcct agcatttccc tacactgtgg cattgggcct tcataggacc 98460 aagggcctcc cctcctcctg atgcccaata aggtcatcct ctgctacata tgtggctaaa 98520 gccatgggtc caaccatggt tggtgtttta gtctttggga gctctggggg tctggctggt 98580 taatattttt gttcttccta tggagttgca aactcattaa gctccttcgg ttcatccctt 98640 aactcctcta ttgtggtccc aatgctcaat ccaatggttg gctacaagca tctacatctg 98700 tattggtcag gttctgtcag aacctctcag gagacagcta tatcaggctc ctgtcagcaa 98760 gcacttcatt ggcatcagca atatagaaaa tgtggttaca tttacacaat ggagtactac 98820 tcagctatta aaaacaagga cttcatgaaa ttcttaggca aatggatgga tctagagtat 98880 atcatcctga gtgaggtaac ccagtcataa aagaacacac attgtatgca ctcactgata 98940 agtggatatt aggaataaag ctcagaatac tcaagataca actcacagac cacaggaaac 99000 tcaagaagga ggaagaccaa agtgtggatg cttcagtcct acttagaagg gggaacaaaa 99060 taatcactga aggtagaggg tgggagggac ttgggaggag gagagaaggg ggaagaggaa 99120 aaaggaggca ggatccaaaa tgggaggaga caggggagat gtagttcaga tgacaggtca 99180 ggagtttgaa cagaggtgtg tagcaatggg ggatggggaa ctggggatat ccaccacaaa 99240 gtcccagatg ccaggaaagc aagaggctcc caggactcta tggggatgaa attagatgaa 99300 atacccaaca gaggggagag acaacctgta gagaacacat ctgaggttag gcatggcccc 99360 catttaagga tgtggctacc tacccatctc aaacatttta acctagattt tctcttgtct 99420 aaaggaaata cagggacata gagtgaaaca gagactgaag gaaagaccat ccagagactg 99480 ccacacttag gaatccatcc cagatgcagt cttcaaactc agacactatt gctaacattt 99540 cttttttgtt tgttttgttt tttgcttttt gtgttttcaa gacaggtttt ctctgtacag 99600 ccctggctgt cctggaactc actttgtaga ccatgctggc cttgaactca gaaatccgcc 99660 tgcctctgcc tcctgagtgc tgggattaaa ggcgtgtgcc accacgccca gctcaacatt 99720 tcttaactat gaaaaaaata acgtttttgt tatgctcaac agcaggtggc agctgacaaa 99780 gtataattgt atgtggtcct gaaacattgt aaataatttt aatgttatta taacattcaa 99840 caaaaacacc caaattattt ttccttctac ttaaatctca aaattatgct accatctcta 99900 atctcaacac aataagtgaa ttctgaagca actaagctag gtggggcatt attggtttta 99960 gtttagaaag cacgcacagt tagtctactg tagcagtgcc catttgtgga aatttctgct 100020 cctttcttca tagactcctg ggtggaagaa aagtgagacc tcaacaacag cacttcatct 100080 ggaactcaac ttccagaatg gagattgaaa aatataaatc accaaaacca aaggggagtt 100140 ttatgtcagt gagtccatga gagtataaat gaccacaatg acttaagaaa tcctcataga 100200 aggtaggcaa gatggtttgg tatataaagg atacttgctg tcaaatctga tttccagccc 100260 tggagaccaa tgagtgaaga agagaaccct cttctaccag ccagttgtcc tctgacctct 100320 gcacaacaca cacacacaca gggggggggg gggagggaga gagagagggg gagagggaga 100380 gggagaggga gagggagagg gagagggaga gggagaggga gagggagagg gagagggaga 100440 gggagaggga gagggagagg gagagggaga gggagaggga gagggaagtg taagaaattc 100500 aaaagacatc caaatgggtt gccagaaaaa aatgcagtta cgtttgtatt tgtaataaac 100560 aacactattt ttgtacttca gaataaatag caggacatct agctatactg atagttaatt 100620 attgtttatt cgaaattcac ttttacctgg acagcttgct aatttctttg acaagtctgg 100680 cacgcttaca tctgaggaaa gtctaccatt ctaaaatctc tctgcaactt gcctgaaatc 100740 cagttaactc actttagccc ttcagcttaa tataaattgc catttgaaat acacacatat 100800 gtctgaggca tacatgagct gctcatgcat caccgtaaat taatttaaag aaatttaaaa 100860 agactgatga ctgatttctt ctcaatatct aatttttttt ttgttaaaga aaattcctgt 100920 gaagcagctg tatgtgcaaa ggttgtgagg ctgactaaaa ctttaaaaac tgtggagggt 100980 aagggatgtt gctgaaccag gaagcttact tcaagtttcc ttggagctat cttttttttt 101040 tttttttttt ttttttggag agtagattct taaaacatcc ttaccacaat atatcctccc 101100 ttcactcttc ccatctcctc cctacatctt ctcccctgca tatccactcc ccctgcattt 101160 cttcttcaga aaagaactgg ccttcaagag agtacagaag aatgggacaa agcaagatac 101220 aataagacaa ggcaaaagcc cgcctatgga ggctggaaag ggcagcccaa taggaagaaa 101280 agatccccaa gagcaggtga aagagtcaga aacatacgca ctcccaccat taggaggtac 101340 cacaaagaca ccaaactcac agccataaca cataagcaga ggacccagta aggacctacc 101400 caaatatcat gccattttag tctctctgag cccctgtgag ccctgcttag ttgactccat 101460 gagccaatgt ttatcctctc tgactcctac catctttacc cacttcttct agttctgagg 101520 ggttctccta gctttgaaga gagagatcca atggagacct ccaatttaac ctctctctca 101580 acacaatgtt ttactctagg tctctgcacc tactcctttg gggccatttt tctaccttaa 101640 ggagacactc cttgctcaac tctatatcag tcctaacatg ttgataagca gattttaaaa 101700 aaataaataa acaacaacaa caacaaaaaa aaccaaacaa aatcactacc actacaacag 101760 caaaaccttt gtaatgtatt aacaaaattt tattcccaac taacggaaga gctcagtagt 101820 tatcagataa catctgaggc ctatctgcct ggctgcagtc tgcttctctg atatacccac 101880 caatgaattt taaaattacc ttgattcatg acttttactt ttctgctatt atagaacttg 101940 gtgaaacagt atccacattg gaacatggaa ttagggtaac ttagtaccct gtttgtaagc 102000 catggccact caaatttggc tccaaagtaa acaatctctt attccctttg aatggtatat 102060 tagttgcttt tctgctgctg tgataaaaca ctgtgaccaa ggagagttac agaaaaggga 102120 gtttattcta gtttatggtt ccagagaatt agagtccaag atggtggaat gaaaacaagg 102180 gagatgaaga agtaactgag cgctcacatc ttgagcaaca agcaggaatg acaagcattt 102240 tttgtttgct tgcttgcttt tggcaaaaca aaacaaacaa ataagaagct ctcaaagccc 102300 agtcccagga acatacttat ccaggaaggc catacctctt atgactcccc gaggtcccca 102360 agtggagact aatcgttcaa atgcttgagg ttgggaagtg tatctcaccc aaatcttcaa 102420 aaggtgggag ctctattttt tgtatcaatg tttgccatga ctaattcggg tctgaggata 102480 taggagattt ggtttggttg gtctggtttt gaaaggggaa gaacacagga ttgtctgtga 102540 aatgttaatt caaactcatt ttaacggttc tgttcttata ggattatcat gtgtcaggga 102600 atgctacatt gaaaacatga gtttggagaa atgaaatgag atgtaagtta aaagatgtaa 102660 agtaggggat atatagggcg gcaagtgtga gagcaaatgt gtaacatgag gacaatagtt 102720 aatggaatgg tgtcatagtc aagattttat aaagagtact tagctggcct tgtcaaaaaa 102780 agtacctata taaactgata gacacattta tctgtttcat gacagtgaac aattttacca 102840 ttctgtacgt atccaataag atcatattga tgctttaaat gtacacagta ggaactactt 102900 gccatcaaag aaagaacaat aagtatgaca tgatagagca taagaaagct ctttgactcc 102960 ataatttaac ttgaaatatg aagccctcag aagtagagct gttgtagatt atgagaaatg 103020 ttataacagg ggcaattgat tttcataaac gatggagaaa gtataataac ctagtaaaca 103080 ggtataattt attccatagt ttgatttttt tctaagagga tgatttctct tagaataagt 103140 tctctttgga gaatgggcag ttattattat tgatgtaata aaaataaaat tactctgtgt 103200 ttctggagga gaagatgaag aagaaaaggg tgaagaaaga ggaggaaggg gaaaaggagg 103260 aggaggagga aggggatggg gggatggtta caaggggcaa aatgttcaca gtgagtttat 103320 gggtctgtgc cttttttttt tttttgtcca catggaagtc ttgttgtcca cgttggaaat 103380 gcagatttct ctctgctcca gacataatgg agatgaatgc ctataagtaa gagctctgtc 103440 attaaacatg gatcagacat tccccaggca caatctaata gaaaagaaaa acagaaaaac 103500 agaaaggagt cagaataggg ggatcaatct gaagaagagt ggagtgaaac ggtttggaaa 103560 tcgaaaaggc aacacaaaga ataatgacag gtcagagaag gtgacaggct taaaagatac 103620 aaccaaataa ttccattttc atgactccat ggtgaagatg aaagaagcag aagccgtttc 103680 aaaagctaag ccaggcaaga gacttgggca ctgaccccaa ggacagtctc acagcactca 103740 caggtttcaa gtccatctca gttcttggtg agacagtggt cttccattgc acaggtctgt 103800 ggcagtgaaa attcctattt agtcactcta tgggaaccag agtgtaggct ctgaaagatc 103860 ttgaaagtct attgctaaaa attgagctaa gaatggaagg ctacgaattt gggaaggaga 103920 acttaggaga gcacaacatg ggaggagtta gaaagatgag aaggaagggg aactatgcaa 103980 atgcagtatt cacctacatc attttcaatg aataaatttt atttatttat ttacttattt 104040 gaagggatta aaaacaacaa cagaatcctg agataaacag ggaaagaaag cgcgggggaa 104100 aaaccataac cctgagagtc tggatttggc ctgccacaga cctagagtag aagaggccca 104160 ggaaggacaa gatgtcccat ggagagcagg atgcccgctg ctgataaact acaggttcag 104220 ttggaaggga gctcagttta ggcaggaagt aagtgcataa ggaaagaaag ccctaccatt 104280 agtatctggg aatagttctc atcaactgag agcaaacctt gtatggagaa ctgagtctga 104340 aatcagtggg tagatgagca gcatgaacca tttctttgcc tgatggccac agagcctgag 104400 aactcaagtt ccagccatga aatacagagc tatattctac tagtaggctc attgataaac 104460 ttagaagttc ttgcatgcat gaagacaggc tctccatcta tctagaaaat gtcttctatg 104520 gtcacttagc acatgcccag tgcacttggg agatacctca cagctaagac attggctatc 104580 tcaggggatg caatctggat tgtctcagtg gggtgacagc attttcccag cacacagact 104640 taaaacctgt gtactctgat atacaaaggg aagccaccaa tctgaaaaca actctggtaa 104700 ccagcagaga gtgtccaaca gagcatcagg aaacttaaac tacaggcaag acatcagccc 104760 acagtttaaa gggctatgat ccccaccatg tcatgtaact ggtaatctcc aattttctag 104820 gacctagaag gaatccattc cagcacttcg cacacacacc ccttcttttt aactctgggg 104880 attcttcact ttccctcttg tcattgttaa gctgttagag gcacttttat tgtagtctta 104940 aaatttgtct tttattctca tcatttaatt atctcatttt gtttatgcat atttttcatt 105000 attgggtaat cttgattttt ttttcctttt tagagtgctt cttcttattc cttatccttt 105060 tagaagtatt ctgatcttac cttttattat tttaactgga atttttaaaa aaaatttttt 105120 ttctaacttc ttaccctgtc ctattcttct ttatgatatt catctccact tggttcgttt 105180 tttcctcttt aagtggtctt cacatctcta ctcccttttc tgtctccttc cttatctctt 105240 tcacttactg catccacatt tacctcaact aaagagtatg actagatctt gaatggtttg 105300 atgttggtgc tgttagagca gtttgctctc tccactctaa ctggaactgg tgaccaaact 105360 ctccagagta agctgcttag ccccatgtgg tggaacataa ctgtggttgt agaaccgagg 105420 gggctgaggc aggagcttag ccccgtgtgg tggaacataa ctgtagttgt agaaccgagg 105480 gggctgaggc aggaggatcg ggctttcagg tcacactttg ctacatagta agtttgcagc 105540 cagcctcctt gtgagatgtc tccaaacaca cagaaacaaa agaggaaaag gagaaaaaaa 105600 tgactgaggt attcaatatg aaatactcaa ataaaacttc aagagatggg acaaaaccca 105660 aaggtataag aagtgtagca gagaaactca agaatgtgtc aaaggaaaca gtatttcccc 105720 caaaaggtca taattctcgg cttctcaaaa gacatggaga tttgttaaca tctagatgaa 105780 gacttcacaa gtttatttga tcaatgaatt ccgagaggat acaaacaagc agatgaattc 105840 actcttgtat ttgcggagga aagtcaacaa cacagaagaa tatgacagtg ggactgatga 105900 gcaaaactct aaggtacaca gaaaatgtca gcaacatgaa agaaagattc agaaggaaaa 105960 ttgagttttt aggggttttt tttgtttttg tttttaaatg aagaaaccaa aagaaaacaa 106020 acaagccatt ggaaaaccac acgacaaatg atttaatgaa ggagaagaag gaatattact 106080 gaaacaacaa aaacccacta agagaacaga caataacaaa gcaattttac accaactaaa 106140 aaaagaaaca agtaacaaaa ttataggaat tagtaaacat ctctcaagaa gaataacatt 106200 atatgtatat agccagaact cactaattaa cacagattgg ccacctagat gcctgtatga 106260 agacaaatta acaacaacaa ccacaataaa aacattgacc ctgttactat ctccaaaaac 106320 cacaccttat gggtaaagtc agccactgtt ggagaatgag acaatctaac aagtgagtga 106380 aatctgaaaa gaatttagct gtcctacatt taataaggta gacattaaaa caaattagac 106440 agaagacata aagaaggcca agtgagcaat gaaagggaca actaattaag atggtatatt 106500 aattgaggca ggcatggtgt cacacaccta gcacacggta gacagaagag gccaatctct 106560 gtgattttga ggccagtctc attaatagtt ccaaaacaga gctacatgga aagactgcct 106620 caaaaaggaa aaagagatgg aggaggagaa aaaggaggag aaggaggagg aaggagaaga 106680 agaagaagaa ggagaaggag gagaagaagg agaagaagga gaagaggagg aggaggagga 106740 ggaggaggag gaggaggaag gggaagagac aaaacaaccg tagatacaca tcaaatttta 106800 gaattcttaa tttcataaaa cactaatgga gacaaaattt cagatacact caaataataa 106860 tagttgataa ttacaatatc atacaataat ttttagatgc attactcaag ctgaaggtca 106920 ataaagaaat ttaaaatata aataggacaa aatgacttaa aggatatata gagaatattc 106980 aatccaacat atgtgtttat aaaagataca cattgttctc agccgcctat ggaagcttcc 107040 tttaataggt aacatgctac atggcaaagc aagtcttaac caatataaaa gaatcaaaat 107100 aattccttac gtcacgtcag atcacagagg aggaaaatga gaaatcaaca gtatgagaaa 107160 ctacagaaaa tacagaaata cattatactc ttttgtatgt gtgtggtata tatgtgtgca 107220 tatgttcaag tgtatgtgtg tgtacacttg catgtggatg tgtaagtcca ttcatgtgga 107280 ggctagaggt caaagtatgt gtgccagggg ctctttctta gtctcttgct cagtttttaa 107340 gacaagtctc ttactaaacc tgtggcttgt tgatttggct agattggacg ggccagcaca 107400 ttcccagcat ttccctttct ctgcctctgc aaagcttcag ttacaggcat gtgctgcccc 107460 tttagccata ttatttagtg ctgtggatat gaacacaggt tctcttgcct cttagacttt 107520 attgacagcc tctaaaaagg atacttttga ataacaagtt ggacagtgag ggagtcagag 107580 aggaagctta aaaatggctg gaatcacaag taaaaacaca ccctaagaga atctttggaa 107640 tagaaaaagc agttctagaa ggaaagtttg tagctctgag tggttatatt aaaaactcag 107700 aaagagctgg gcatggtggc gcacggcttt aatcccagca ctcgggaggc agaggcaggc 107760 agatttctga gttcgaggcc ggcctggtct acaaagtgag ttccaggaca gccagggcta 107820 tacagagaaa ccctgtctcg aaaaaaccaa aaaaaccaaa aaaccaaaaa ataaaaaaac 107880 aaaaacccaa agctcagaaa gatttctcca cagtgagtca caactggcta aggtatagag 107940 atgaagaacc tgcagaattc tcagcccaaa gggaacataa ttactgtaac ccccacccct 108000 caaggcttag ggatgaacac agaagagtct gtggtggtgg atgccgacca cacgaagcat 108060 tatcatctga acactgcaga ggcgctacac ataggaactc agttcttttt cggcggagta 108120 tacaggtata tatactgtat atagccagac caaatcccag cagggagaag ggagttgggc 108180 acaatcctag ccaaactctg gagtgattga caattgttag ctgcgagtat agtgtaacct 108240 ctccttaggt gagtactctc cagtagaaga caacacatca aaaggctttg caaggctaaa 108300 aagacaatgg gtacaaagtt acatggataa agaagtggtg ttgaaccctt ctcaatagtc 108360 acaaataata taaaatatct tggcatgact ctaactaagg aagtgaaaga tctgtgtgat 108420 aagaacttca agtctctgaa gaaagaaatt aaagatctca gaagatggaa agaactccca 108480 tgctcatgga ttggcaggat caacattgta aaaatggcta tcttgccaaa agcaatctac 108540 aaattcaatg caatccccat caaaattcca actcaattct tcaacgaatt agaaagagca 108600 atctgcaagt tcatctggaa taacaaaaaa cctaggatag caaaaactct tcttaaggat 108660 aaaagaacct ctggtggaat caccatgcct gacctaaagc tttattacag cgaaattgtg 108720 ataaaaaccg catggtactg gtatagtgac agacaagtag accaatggaa cagaattgaa 108780 gacccagaaa tgaacccaca cacctatggt cacttgatct tcgacaaggg agctaaaacc 108840 atctagtgga agaaagacag cattttcaac aaatggtgct ggcacaatgg gtggtaatta 108900 tgtagaagaa tgcgaattga tccattccta tttccttgta tgaaggtcaa atctaagtgg 108960 atcaaggaac tccacataaa accagagaca ctgaaactta tagaggagaa agtggggaaa 109020 agcctcgaag atatgggcac aggagaaaaa ttcttgaata gaccagcaat ggcttgtgct 109080 gtaagatcga gaattgacaa atgggacctc atgaaactgc aaagcttctg caaggcaaaa 109140 gacaccgtca ataagataaa aaggccacca acagattggg aaatgatctt tatctatccc 109200 aaattggata ggggactaat atccaatata tataaagaac tcaagaaggt ggactccaga 109260 aaatcaaata accccattaa aaatggggct cagagctaaa caaagaattc tcacctgagg 109320 aataccaaat ggctgagaaa cacctgaaaa aatgttcagc atccttaatc atcagagaaa 109380 tgcaaatcaa aacaaccctg agattccact tcacaccagt cagaatggct aagatcaaaa 109440 attcaggtga cagcagatgc tggcgaggat gtggagaaag aggaacactc cttcattgtt 109500 ggtgggattg caagcttgta caaccactct ggaaatcagt ctggcgattc ctcagaaaat 109560 tggacatagt actaccggag gatcccacaa tacctctcct gggcatatat ccagaagatg 109620 tcccaactgg taagaaggac acatgctcca ctatgttcat agcagcctta tttataatag 109680 ccagaagctg gaaagaaccc agatgcccct caacagagga atggatacag aaaatgtggt 109740 acatttacac aatggagtac tactcagcta ttaaaaagaa tgaattcata aaattcctag 109800 gcaaatggtt ggacctggag ggcatcatcc tgagtgaggt aacacaatca caaaagaact 109860 caaatgatat gtactcactg ataagtggat attagcccag aaacttagta tacccgagat 109920 gtaagagaca atttgtaaaa cacatgaaac tgaagaagaa cgaagaccaa agtgtggaca 109980 ctttgcccct tcttagaatt ggaaacaatc acccatggaa ggagttacag agacaaagtt 110040 tggagctgag acaaaaggat ggaccatcta gagactgcat catagagatg ccagggatcc 110100 atcccataat tagcctccaa acgctgacac cattgcatac actagcaaga gtttgctgaa 110160 aggatcctga tatagctgtc tcttgtgaga ctaggccggg gcctagcaaa cacataagtg 110220 gatgctcaca gtcagctatt ggatggatca tagggccccc agtggaggaa ctagagaaag 110280 tatccaagga gctaaagaga tctgcaaccc tgtaggtgca acaacattat gaactaacca 110340 gtaccccgga gctcttgact ctagctgcat atgaattaaa agatggctta gtaggccatc 110400 actggaaaga gaggcccatt ggacattcaa actttatatg ccccagtaca ggggaacgcc 110460 agggccaaaa agtgggaatg ggtgggtagg ggagtgaggg ggagggtatg ggggattttt 110520 gggatagcat tggaaatgta attgaggaaa atacgtaata aaaataatgt aaaaaaaaaa 110580 gaaatggtgt tgacttacaa agagccaaga gaggagtcaa atatggtcaa accacattat 110640 tttgcagttc tcaaagaagt aataaaaaaa atcgaacaca tttcctaata ttgtacatca 110700 agcacttaca aaagtaagaa caaatcatat gccctaacaa gaaacaataa taatcagtgt 110760 gaaaattaga gagaagctta aaagcaatac ataaaattaa taaaacactg ggataatcct 110820 ttttaaaatt aaaattgaca aagataaaga aagagaagat tcagattagc aaaattataa 110880 atgaaaaagg gaaggccatt tcagtttcta acacaattta aagaagcatt agagaatatt 110940 ttaaaaagct gtactctgaa acctggcttc taattttagc agaaacctca catagggtct 111000 ccaaagccaa ctctgagcct ggttggtaaa gctttctgtc cttgctagtc agtttcttat 111060 cattaagcaa tctgggattc aaagacttta gcagtgaata tttccacttc agtggttgtc 111120 ttagtcactg ttctattgct gtgaagagac accatgatca aggcaactct tataaaagga 111180 agcttttaat tgggggcttg cttacagttt cagagtccct tatcatcatg gcagggagcc 111240 tagcagcagg cagacaggca aggcactgaa gtggtagctg agagctacat cctgatttac 111300 aagctggagt cagagggaga aaagaaagag gggaagggag caagggaggg agagagagag 111360 acagagagag acagagagac agagagagac agatatatat atatatatat atatatatat 111420 atatatatat atatatatat atagagagag agagagagag agagagagag agaaagagag 111480 agacagacag acagacagac agacagagaa tgagagtttt gaaacctcaa atctcagccc 111540 cagatcacaa atcctacaac aaggccacac ctcctaatcc ttcccagtag tctaccaact 111600 ggaaaccaag cttacgaacc tctgggacca ttctcattcc aatccccaca aagggcttcc 111660 accttgttaa ttttactatc aacgaaattg acttttgact ttgacaattg attttgtata 111720 caaagaaact ctagaaaaga aagaaaacgt taagtcatac cactaaggat caggaggcag 111780 ccctggacag ccgccacagc agaaaggctg gcccttctat gtttctgtga atcatagcat 111840 atgcgcttgt aagaagtgaa ggatatttct ccattcaatt ttatacatga caaaaaatat 111900 tcctaccaaa tgtgaagtgg caagtatgaa tttagtgttt agttctcctt aaacagtcac 111960 cagaccttga ggtcttcctc aggttaccac agcttgtagc attcattaag cagaatggag 112020 gaattttatt ataaaatgta actaatgtat tatatgttat tatcattaca aacccttgta 112080 tgtaacccag agagggaata cacactatgg atctgctcca actttttaat aagtaaattt 112140 tagttaaagt ctatttaaag caaactccta agacattaac cagctcccaa gagctgacta 112200 ctacatgtta tgttagcttg tccatggtgc tatttgttac tcttacagga tttctctgtg 112260 tagccctggc tgtcctggaa ctcactctgt agaccaggct ggcctcgaac tcagaaattc 112320 gcctgcctct gcttcctaag tgctgggatt aaaggcgtgc atcaccacgc ccagctacta 112380 tttgttattc ttaaatagct aaccacagca taaaatttta ttttcctaaa atttacattt 112440 aaaagccatc caacttacca aagtgatttc aaaccacaat tacattttat ctcaactacc 112500 agcattttat ttagccagga tctacatgag acacatatca tgatgtgcta tgtacatctt 112560 gttatacagt gttatattga taacaaatgt catcaatata acattgaatt aatcttccat 112620 aatttatggg gaaaaaagga gcagccttac tgaagggcaa agttatacaa cagctttaca 112680 gaagctgcat gcgagtgcag taccgggaca cgggcacgga cggcggcact ataaccattt 112740 tccgtggtgg taatcttgct ttcatctgac acagaaaaga gaccgccgtt ttgaaaactc 112800 acagaactag cctcacggtt ttgtgagtcc attgagcgct ggctgcgaag aacggtgttt 112860 aactcgagaa atcattgaac aagttttaga aaataaagat gcttatgaca atttcaaact 112920 tgaaggtctc caaagaagga ctgagatatt ggtgagagga gtaaagagaa tcctggtgca 112980 tttatttcat gcttccttct gttcgaagat cattttgagg tttataaaag gtggggtgat 113040 ccaaaaatct ccaggctgag agtcctggct gaggctgtga actgggctgc agagaaaggg 113100 ccacgcctcc ctcctctgct cgcattactc agcagctttt ctgcatgtgg ctggctgcag 113160 acaatctaaa cccttccgct gtcgctcccc ccttatactg ttctgccaaa aggaaggcag 113220 agaggaaatc agctacgggg caaagactga atagtgaaca catacagcaa tgtccagcga 113280 gttacctcct gtgtcttatt tatttattta tttatttatt tatttattta tttattttct 113340 ctaccgattc gctaaaatca taaagagaat gcttctgtct gacatcttgg accaaaatgc 113400 ttcccatact gcactctgta acttttcaat tgaatattaa taactaaatg gatttataat 113460 ccattatttc cctttggtca cctactcatc acggactaaa cgaaagggca atgccattat 113520 cttcctggcc caactcttaa catacgtgtc attgccaaat caaaggaaac cttaccactg 113580 agcaattcac agaacttcgc ttagctaata tgcttaagga atctgagaat gtcctactaa 113640 attttaattg aatgaagacc ttttagaaga atttcttctg tagataaata aacctagagc 113700 taagaaagga aagctacatc tacaggctcc atctcaaagc tatctatatc tgtagtcagt 113760 tttcagggtt cctacataga gaataagtat gtgttgaaaa aatactacac tagtaagcag 113820 cctttacatc agtggttctc accctgtagg tggaaatcct tttgggatta gaatgacagt 113880 tttacagagg tcacctaaga ctatgaaaaa catagatact tacactatga ttcataatag 113940 tagcaaaatt acaattatta agtagcaata gaaagaattt tagagttggg agtcatcgcc 114000 acatgaggaa ctgtgctaag gggttgcagc atttggcagg ctgagaacca ctgctttata 114060 ctaccaaaat tttggaagaa agggagtgag ttcattcatg gccaagtaca attgctaaag 114120 atggagccaa gattaaactg atctaagcaa gagaaggaag tatttctgtc ttggagtctt 114180 agcttctcag tcatggacat tccttgatgg tatctttcca cttagaatat ttagggttct 114240 gaaccctatt tctgaatgcg atttcttgac ttttcttggc ttcaattcca tcacttctga 114300 agtctataaa tactagagcc ctatatagcc ctctactcct ttaaaatact gtcctcaatg 114360 gtcgcttgca cacagaaaac tctacatagg ccacgtgact cttagcttag ttagctgaga 114420 aaatcaggaa ctctttctga gcaacactaa attgggctga gaatgagtca gaaaagtcaa 114480 ggaaacatga actcaaagtc atctagagtt gaattctggg aagtgaagct tagagcaagc 114540 aaaggaccat aacaacaaaa gagaggccta aataaataga tagataggta gataggtaga 114600 tagatagata gatagataga tagatagata gatagataga tagatagata gatagataga 114660 tagataaagc aaagcaattg tcgagtcacc aggataaaga ataggttcat ctgcttatgt 114720 ggccaaattc tcaggggcac ttctgcctct gccttagtcg tatttcggct cttggctctc 114780 tgattgtatg cccactatta atgcaccaat tacttatatt aagttgaaat aagctcttaa 114840 tataagtctt ctgtggccca aacataatgt gaaaatcatt ttcatgtcac actttaatta 114900 ctcataattc tatctttgtt tctttttatt tgtgagacac agtcttgctc tgtaacctaa 114960 cggcctgtaa tccactttat agtctaacct ggtcttttat caccctgcct cattttcctg 115020 gtgctgggat tacaggcatg agtcacaaag ctgggtagat tcttcagggg tttttttttt 115080 tttctttgta ttttttaatt tattttctgg caatctcact cgtgtccatt atgtgtgttg 115140 atcatttttt atcatcctgt tcgcccacac ccaatgaact tcttattcct aatacattct 115200 ttcctagttt catgtctctt tgttggaagg tcacagactg agtgtaatta aagctgtttc 115260 catgaacacg gcattttgtg gaggatggtt actggagcat ggacaactga caagtggctt 115320 cagcattgaa tgaaatacct gctttaccac agtggcactt aagtgcatgc tgatggcccc 115380 cttgggtgag ggtggacctc ctaccatatg tcattaaata tcatgggctc catcttgtgt 115440 aactaaccat agccattgtg acttggctat agcagagtca tatccaggaa acaaggtttt 115500 cagaactcct tttatgttat ttctttccta ggagtcgttg ctcatagagg ccccagtggc 115560 aggcccataa aacagtagga gctatagcca tcgcctttgc ttgctcatta gaagtggatg 115620 ataggaccct gttgctgaag agattgcagt cttcggttac agaaaataga gaaatcgagg 115680 cgggactgac ctagaagctt cctccctttt gcttagcatt tatagtccca gaaagtgctt 115740 ttgtaagctg ctagtgaaga aagtgatcaa tggcctaaat cacttgtgac caacctacca 115800 ggacaatgta cctactggtg caataatcac agggctgatt attatgaggg taaccaactg 115860 gtctttgatt gtatctgaag cctgcttcac aagatggatt catgcctatc actgttaaga 115920 ctggtcctaa gcctatggcc agggaattca taggtactaa tgagggagtt agaactgttg 115980 ctttgctaaa tgccatgctg tcaaattact tcccaaatac gtttgtttat gcccatagat 116040 agtgctgctc tcaacctcgg ctagagaatc ttcatcttgt aatgggcaaa ggttaatatg 116100 gtcactcata aataaccatt tcttttagag taaatgactt tgagtgctca cccctaaatg 116160 aatcatctct accactttct gagtggctca tggaacatgg tagaaggatt tctatgtttt 116220 tactatagag aataataaaa aagttcaaca aaatgaaata ttataaatac ttgagtgatt 116280 tgccctatgg tataataatt tttcaatact tgttttaagt ctggaaagtg ctcttctact 116340 gatttaaatt actgttttaa gtactgaaac taaataatgg cacatacata tggatgacat 116400 gtggaaacaa tttgcatact gagtaaaaat attaataaaa taacataaag tggaaaatca 116460 ctcatctttt aaaactgggg atattgctaa atatagattg tgtgtttagg aagcccagag 116520 ctgtgggcct gatccttaga gccacattat aaataaagtt aaagtaaaaa aacaaaacct 116580 agacattcag tagggagatg ttttaaaacc ttggtgacct tgtaggtatc tttcaaaaat 116640 tgtatcatcc caattattca tattaagaat attttttaaa gtgccacagg taaaaaatct 116700 tttcttaaaa aaagccttta acataatctc tagaatttgg atcaacaaca ttgctgagat 116760 attaaagttt catggtacaa attatgacag aaaagtttga ccaaaaataa agcagccatt 116820 gttgctacag tttaagtgta agaatacaat agaatgggtc ttggagagtg actgaatttt 116880 acagttttat aatcttttct aatgaagtac acaccttgta atcattcaat aatttgaaca 116940 gttcataata ttgtttaacc aatttagact gcaaagacct cggtctgaca gagcaagtct 117000 tgacctgctt aacattatgt tatgctagtc attttaaaat gagtctttat ttcccataga 117060 aggtcagttt ttttacatta ttatataatc ttttgacaga ataacaaata acattctgaa 117120 tgtctcattt ctaaatacaa aacatcttag tataaaatta tgcattgttt taaatgcttg 117180 gaagtaggtc cacatgtaga aaacaaagta cgtatgataa aaaatatcaa aattgtatat 117240 tcagcaggca tattattaga aattgtacca cccggtgatt tattagttac taggaaaact 117300 gtagagctaa accaaaaagt aatcattaaa taacaatcaa tgagtcaacc aattgttaaa 117360 gaaccaaatc tataggcaca tatatattac aaggcatggg gtaaacagag atttgcagtg 117420 tgctctcctt cagttatgaa ctgtactgca taggctgagg gatcaatcta tggcatgcca 117480 tgcctcttca ctttccccat cagctgtaag gaagcacaaa ggcgaatccg ggccagcaaa 117540 gaataatgct tgagcatttg acatttcacc acttcctgta gcttgcatgc gttttattac 117600 actctttgac acaatatttg attttacaag ttggatcaag ttgtttagtc agcaaaacag 117660 gaataagcaa atgagattct acctgcctac aatttccgtt catctccagc cgtctgtctg 117720 tccaccggaa tgaaaactgg agcatactca catcacaagg ggcacatgca tcagcgtgaa 117780 tgaagctacc atacctccct ttggtttcct catctccaaa atggaatctc cttttcagta 117840 ttttatcttt actgatttat cataagagct gtatgattct tacctttttt gtttacttag 117900 cagagacatc agaatagtag aaggaagatg aacaatgaga taatgctgat tttgtataca 117960 aagtacaact cttagtaaaa aatgttgttg ctttcagtgg tataacaatg ttattaaagt 118020 ttttaatcca tgtctggctt ttttgttgtt gtttactttt atctgtctgg ggagtcttgc 118080 tatgtgacag acttgtttag atctgactat gtgtccagtc tggcactgaa ctgaacagtg 118140 attcccttgg tcctcttacc tcgaacccta agtagtcaga gtttacattt gaggcaccat 118200 accaggattt gcgtttgact tcatacacat aactttaaca ttttaagatg gggaaatgca 118260 acaaaatatg ttcttttcat aagaagagag tttatagctc tcctattcct gtcattaaat 118320 ggaaataatg ttttgttgat gatttattaa gcaaacacga ttgatggttc cttcaagttt 118380 gtgactggcg tctcaactgt gttattattt gtagtagttc ttgaattaaa gtgtatcagt 118440 ctacggatga cattccaatc ttccctacct cgatggacca gtttataaat ttgaaggctg 118500 atctgtttca tgttcctact tttccctgaa agtattcata cctttttacg acataccact 118560 tacgcatttg cttttcattt caacattctg actaatggta cttattaaac agctacagtc 118620 tggttcaatt cctgaagatg ttagtacatc gcccctggat ctcatagagt tgttactaac 118680 caagtagaac ctcacagata cgcctgggac agtcctaaca cagagaccaa tagttataga 118740 aaatcaaact caggtttgtc acgagggctc taagaatctt tattgtaccc tccagctttg 118800 gttcattgct aatacatgct ttataggcaa ccataactcc ctaaagaaac atacatagag 118860 tggtatccaa taaaattaaa gtttttcaaa gaggtccttt cctcaccaaa gcctgtggac 118920 agccagtgtg catggctacc atcagtcgcc actgatgatt ccccttgtct catggagcat 118980 tctcccctgg tttctgatga aaaagttgcg aatgggtgag agaccatgcc tcttaaaagc 119040 ataggtagat atatgatagc tgatcaatag ataagtagat gatatattga tagacaacag 119100 ccttcctaaa gtgtggctaa gcactattta ttacttctgt cttggtccac atgtttattt 119160 actttatctc acaaggaaat gaaattgatc cgacaccacc tccactcaca agttatcctg 119220 gcttttactc tgtgctgttc tggatgactg tcaatgtaaa tacatgaggt ttgtgttgat 119280 tttgttttgt ttttgttttt ttttttcttt agaagaaatt ttaagatatt ggatgaagat 119340 gaaagtcgta aggctattta acctcttttc tcaaggagaa tattccaaat tttccttttc 119400 ctagagttag atattaactt ttaaaaattc cattaaccat ttagatataa atctcaacat 119460 cttacattca ttttatatat ttttaaaaat cggcaaatga atgacaatta cattttgctt 119520 gtattttaaa attcttctgt ctacttttgg cctagaagaa aatgccagct tttagaaatc 119580 ttttgtatca catccattaa tccctgttaa cttgctccct ctaaatacta gtgtttgtaa 119640 accttttcag gtatctccag atagctggtc taaacaggaa tcgtttaaaa cctttcatat 119700 gtaagattat catattatcc tcaattggaa atacagactg taaaaactat ttaagatata 119760 caaagccctt acattcagtt cttgatttta agtagtcttt tagagtacca gtagattaga 119820 aaatacttat tgctaatgaa gtgctctgta gaaatatttg tgttcaattc acattattta 119880 cattgctttt ctctcaactg ttttttatta taatttatga tgtgaatgat agtgtattca 119940 catgtacata tatgtttatt aggggtaggg tagagttacc atcaaggtag agaataacat 120000 cttttcagtt agtgatttag tacttgtaaa acttcgtatt caataaaact gcattaatca 120060 ctatcattat tagtctataa gcttatttat atattttact cttgaaacca tttactagca 120120 aactactttt ccattataca ttttaagaag ttgacatttt agcagtgcta tcattttttt 120180 actcataaaa taaaaagcag gatgtaataa tgtcaaaaat tggaatgact gtatgcctaa 120240 atgtcactca gcatggataa ccattaaatt gacacaccca tctacctaag aaagtattga 120300 ggtgattaaa ccaataacat gaaaatattg acactttaaa tgtagaacat acggaaaaat 120360 gatgttactg agtcaatgca tatttataat gaaggatttc acttaagact gaagagttgc 120420 attacactct gcaatatatt tgttgattta aagataaatt attaagatta aatataacaa 120480 tttatgtaat tccaaatatt ttatcattca tagtaaaaga tactttttag tatccagaag 120540 ccattgaatt gtagagacat gttttgtttg ttaagtccga gcaaaattat ttgataacgt 120600 accattttaa atatatattg tgcccataga aattaggcac tgagaaagta atactcaacg 120660 aatgaaattt cagtgatttt tttttttaga gctatctatt ttgtaggcca tgcagggctt 120720 gtatacatgg cctggtttaa taatattaaa aaaatgaagc agtttgaaga actgcttacc 120780 atgttgggtt gggatacgta agagtctatg tgagtgtgtg agtgagcgta tgtgtgtgtg 120840 tgtgtatgta tgtgaaacac acaacttctg ctttgaagaa agacacggtc tattaggaga 120900 gacacactgg acattatttg cgatggttga ttttaatgtc aacttgccac aaattcacat 120960 cctctgagtg ggaagcacca actgaagaat ggtcctggtc accttaattg atgtggggaa 121020 acccaccccg ggtgtgggta gcagattctg gtagccatct agataaagag agacttagtg 121080 gaaggaagct tattcacagc ttgctgacct ttcctcttgc tgttgagttt actgaccatc 121140 tggtttctgc agctgactcc tttattgatg atcaggacca gtggtaccca aatacctagc 121200 ttccaccatc gactaaggtc taggtacctt ccagatacct tccatgtttt ggccactata 121260 tggagactgc tgaggcaccc agccttgtgg atggagcaac tactgcattg ccagccttcc 121320 cagtgtgaga cagccactgt ggaagtaatg tgattgctaa agtagcctta agaaccaagc 121380 aataacaggt tctgaggctc tctggtgtga gctagttgtt atttctattt taatataaac 121440 tgtataaact gagtaaatta tacacacaca cacacacaca cacacacagg cttttgaaac 121500 acagaaatac agatgaggat gtgattaatg attaattcct ccaggacact gggagaggaa 121560 aatgttgcta agaagcttcc tcggtaggct tgaactcaag ggcaagacag tatactagga 121620 agcaaaggaa agggctgtgg gtataggagg catgtaaaat taatataatg ttttgatatt 121680 taggagaaaa ttgcaaaaca aaatgatgac agtgtttgaa agtgtttgat cagtgccaag 121740 catcacttta tgtacttggc aaacatgact tgaggcctta agctgtgatt tgcaaatgta 121800 gattggaatc aagatcttta tagatgagga agcaaaaatc agaagacaaa ataacattat 121860 caacttgatc tcatgtgcag ccagggctga actgcaaatg ctgatttgcc ccagtctggg 121920 ctcctcaaat cgttccttgg aatcctatta gttggaactt tatctctgct cgtggcaggg 121980 tgcctgggac catgtttata aatatctgct gaatgaagaa taagtgagtc aatcgaacca 122040 gaactcactt tggttagtta atttcattcg tggtatttat ggagagcaga agaaagaatt 122100 ccagagacac gatttgtcaa aactctctaa agaaaatgat gacactatat attgatgaaa 122160 atgaatgttc ttgttcttgc tttatttgat tttcttgtcc ccccactccc catctgctag 122220 ggtctcatta cagcatagtt cttgaatatc ccaggttgac ctgaagttac aatatattct 122280 tgatttagat ggcagacatt gggaatattt tgactcttaa aatttaatag ctaatctttg 122340 aagaaaatta aaatagtgat ctccattttg tagacaagaa agacaaggaa gagagaattt 122400 tacaaagaga tagcgaacac catataacgt catagcataa tctagtttgg gaagaacgga 122460 gggccctgaa gcaccatggt gtttgccagt aatcactgta ttggatgtgt catgctgaaa 122520 tgcaatacaa ttaggctggc ataaaagcta acttcacatg aagaaataga gactttgaga 122580 aatctcttct gaagaagctt gtctatgtgt agaaggatga gacgttattg agcccagtgg 122640 gaggctttat caggaagggg tagatgtctt atatactgga gaaaaaaaat gctgtaaaac 122700 taatcaaaat cctggaatag agagtggaca tgaagactgg ggtacaggga gcccatgagg 122760 aagaaggagc tgcttcaaaa ctcaaagaca tggtgttcta ccttcctaca acgtgtcttc 122820 atctgtaaat cagggtttaa atttgataag gcagaaaaca gtcacaagac tatggtctgc 122880 gtccatccaa tcagctttaa ggttcaattc agccctatat cttttctata tctgatcatt 122940 tcccttcaag gtattcccac ttaaaagcag agtagggtac atattatcaa tggatttatg 123000 attcttggtc aacagttcaa cagaggtttc tttctttatc tctttgttct tttgtttttt 123060 tctttgtttc tttctgtctt tgtctgtctg tcttctcttc ctccttccct cttttccttc 123120 cttccttcct tccttccttc cttccttcct tccttccttc cttccttcct tccttccccc 123180 cttcccttcc cccttccctt ccccttccct tcccccttcc cttccccctt cccttccccc 123240 ttcccttccc ccttcccttc ccccttccct tcccttcccc cttccccctt cctccttccc 123300 ttcccttccc ttcccttccc ttcccttccc ttcccttccc ttcccttccc ttcccttccc 123360 ttcccttccc tccctccttc cttccttctt tctttctcat taaggtttga aataaattgg 123420 ccacttagtc ttgcctctgt agataaggaa gcacagtgct gcttgtgtgc aggtaaacaa 123480 taacaccagc accctgaaaa agtatttccc aaggaataaa aacaactcca aagactttat 123540 ctgtgggaga gtaattctga tagaaaatta gataatttct cagcttatgt gtgatgtttt 123600 aaaagacctc aagttaagtc ctaagagaaa cagtttttat cttatgccca actcacatgg 123660 aaatgccctt agcaatggta tttatagtat ccaaaatgta caattcacaa atgtatcatc 123720 aatagatggt gacggttaaa caagatgaca cttagactag agaatgagtg gaaaataatg 123780 tatgtgacac aagttggata aatctcaaaa acattttagg tagaataatg gattatacaa 123840 taggacataa tgaatagttc tgttatgaaa tgtctagaga cagcaaatgt tcaggggcag 123900 aaggtaaaaa tccagattgc cttggattga atggaagtcg atatttggta tttttgatac 123960 ttgatgtaca tgttttaaaa tgattgcaat gatgttttta caactctaat tgtatttaaa 124020 agcactgaac tacaaaaaga taataaaatg attcttacat atcttcaaaa tttcattcat 124080 ttctcttttt atgaatttaa ttatattatt actggtgtgt gtgtatatgt gtgtgtgtgt 124140 gtgttacaca tatgtgtgaa ctatggtgca ctcatgccat gatgtatgtt tgtaaaaggc 124200 agaggacaac tttcagagat ggcctctcag atccttgcag tataggttcc attgacttca 124260 ctcaaggtgt taggattgca tagcagtggt tgctcagcca tccttctggt attctttctt 124320 gttttagaat tgtaatgtct taattatttt tctactcagt tacattagtt aacagcaaat 124380 aagagaatga atgatgagga aattatttat tactatgcca aacttcctgt ttcacttgga 124440 gccccaatat tatgaatact attacagtgg cctaaagagt gttattggtt cagtgtctta 124500 actgatttgt taaaatgact actttaaatg tgaatcatag atataatgct aaatataatt 124560 ttagaagagg cctctataat atgacatata agacagtcaa ctgttctttt gactaggagt 124620 cctcaacttc aaatcgcaca agctaagaaa gtgcagaaga tgaggattcc agtgagctga 124680 cggggtggtt caatactttt tccaaggatt tacactctgt ggttccatca gcaccaatgt 124740 tagctgacca ggatggctgc ggctcaagag tgtgacatct agagaggctg cagcagtaat 124800 aaggaagacc tttatttccc cttgtggcgt ttgcccaggt gagaagtgtt cttccagaag 124860 cctgactgca gattgccctc atatttcatt aatgaggtca ggagcccaac acttattcaa 124920 tccctggcaa gagcaatgaa ctcgcaaaca agccctcccc tggaattttt atgaaattaa 124980 ccaatttcct aggtcttctg gatatataac ccagagggga gagccataca gaattacagt 125040 cctactttag acagatgcta tctattctat tactaatgta ggaaagaaag gcaaggtcac 125100 ttaaatgtcc ctgaactcac cactaatcaa ggtcatacag atgaacttga acatagcatt 125160 attttttaaa agccatgaaa tttaagatta tctctaactt agagttacat attataatta 125220 tatttaataa aatatatatc attgacggtg gatataaagg actaccgttt catttaaact 125280 aataattata gtaattttta atattacaga gttgccagct ctaaatggga tgtgtccttg 125340 gagctcagag aaccctttgg aagaggaggt agaaagggtg taagagtcag gaatggagat 125400 cagcaggaga acacagctct gtgaatcaac tcagcaaagc tcatacaaac tcatagagac 125460 tgaagcagca agcacagggt gtgcatgggt gtataccagg tcctctgtgt gtatatatat 125520 gtgtgtgtgt gtattatata tatgtgtata tatgatatat atgtgtgtgt aatatatact 125580 atatatacac atatatatca cagctttcag tttagtattt ctatgggact cctgcgtgtg 125640 aatgagtgga cctctgattc ttaaacctac tcttgtggct ttttatcttc tgtttgtttg 125700 ccttgtccag ttttgacgtg atgattttta tttcatcata ttgtatgttt tattttgtta 125760 tgccttagaa gcctgttctt ttctaatgac aggcagaaac ggaatggatc cagattgaag 125820 tggagaggaa ctgggatgcg gaaagaaaga atctgtttat aataaaagag aaaatactac 125880 gttagtctgc tttaatatac aatgtggttc ttagatcgca agaaaaatat taatggcact 125940 tttgccttag gggagagcaa actttcaaca atacatattt gaagaataaa taacaatttg 126000 ggaaacgctt tactatccct cttctgaatc taatattatg caatatgtta tgaaagagaa 126060 attctaatgg atattttaaa tcccttaaaa atgttcagct gaagagtcca gtgttagttg 126120 ctgctagaaa aaaagttaaa aacatgagaa atcaattaga cactgtaatt ctacaggtta 126180 ttactgatga tgtaaaaatc attttgtctc tcttcttgaa agttgaaaag gtgaagtagt 126240 ttaatgaact ataacatatg ttttggataa atggtggcag agtgaaagaa agtgtcaggc 126300 aagtcctatg tgtgcttttc agccaaggag aaccaagcac aagagagggg tggagaatgg 126360 tcttaacccc agtctacgcc caagcccttc tcgttttatc ttgtagatgc taaaaagatg 126420 ttgttggagt tccgttgtct cagcaaaagc acagatttgg agttgtattt catatttctt 126480 taaaaaatat ttatgaatgt agtgttctgc ctgaatgtat acctgcaggc cagaaggcac 126540 atcagatctc attatagaca gttgtgagcc accatgtggt tgctgggaat tgagggaatt 126600 gaactcctga tctctggaag agcagtcact gcttttaatc accaagcctt ctatccagcc 126660 catgtttgat atttttaaag taattgacat tttaaacttt ctctcaaaag tcatgatctg 126720 acaaattttc catgacgata ggagtgattt tataaattta aaactattag taaaaatgtt 126780 ttaacattat attatttttt ctgatggcac taaaaatatt tgaatatatg gcacatggca 126840 tatattgaaa acatcataaa atcctattac acaaaaggaa taatgtagag taaaatacta 126900 aatattaagc aatacccatg attaatatgg agaataagaa attatgagat catgaatatt 126960 attttcttct ttatgcattt acaaatgctc tgtttttata atagcattat aagtagtaaa 127020 tttataacta tgaaaataat tgggttatta agagttggct ccaagccaac atcaatggat 127080 gtctgaaaaa tgtaaaagaa gaaattaaaa ttttgagata gtgaattaag tcataagagc 127140 tgcagattgt cacttgagaa aaatgtcaga ataaattaga agaaagatat actgatggga 127200 gtgtatctga gtgatataat cagaatctgt gtgaaataat ataaaattat tatatgcttt 127260 tcaggtatat tttatataat ggtatttata aaacatcctt aaattataga tttagtaaat 127320 atgtaagaat aatgtaaaac ttcttatttt ggtttcattt aacttacttc tgttgggcaa 127380 ttactgaaca tacaaagttg aaacagacag tggtgacagt accttgtcac acacaagata 127440 ctaactacat cacactgcaa agaaggtatg gagggaaaga caagcagaca ccacacagtg 127500 catacagttg gtgctgtgat ggaagtccac actgggccta ggcacatctc agaaggaaag 127560 tgactcctac tgaggggaag gagaggtcat gatgtcacag agaatgaaca agtttcgaag 127620 gcttggaagc agcttcaata actcacagac acatttactt ctacaggata gataggccac 127680 agggtaagag gtaaacctag acagctcatg gaagccagtc atcttgcatt ggatttttaa 127740 accctgacgc cacatttaaa taatggaaga tttttgttgc tgttgctgtt gttgccattg 127800 gtggtgtttg ctttgagata gcatatcact ttttagccca ggatggcctc aaaattcata 127860 gtgatcttct tgctgaaggt gttctagcag gctctggcat ggcaaacagt acacacaggt 127920 ttgcactttc acatcttttc ttctcccttt ccccaaggtc tattccctca tttggctact 127980 gattcattcc tgagatgaaa caccgagggc caactataag aattaattat ttggctaata 128040 tgtccagtca ggatttacta attcactcca gcacatattt ccccctttcc cctttaaaag 128100 ctcaatcatg aagaagcatc cccttgcttc ttttgcccct tgctctctga tttcttttgc 128160 tttcttactt gctgctatgt tgccttagca gcagcttgac catctccctt cccccgcagc 128220 cccacattgc ccccacctgc tcctcctagt taataattcg gtgtactgag aatttggttt 128280 aagagtgccg acctcccttt cagtgatgct atgacttgga tcaggactcg tttctaggac 128340 ccccgatcca gttctcctaa tggccattca tttcatctca cagcagctta ttggtgaggt 128400 ttctcttact acccatccta aaccttcccc gaatcatcgg atgattactg ttgaatgtct 128460 agcatccctg ctctgtcttg cgcaggtggg gagaatgcat ctccccacat accccagcct 128520 tcagtggcca aggtggactt ccttggatgg tcttcaggca catcccattt cattcagctt 128580 ggtttggatg gcagttgtct ttttcacttt tggttgctat ccgtttctaa ccatctgaaa 128640 attctatcga caagctccag atttctcctc agtccactgt gccttcccct tggtgatgga 128700 gcttgggtga cgacccctcc tcactgaggc tcttatgagc caggagatat cttcagctct 128760 ccactctggc tcaaggccac cactagcaaa ggaaactgac tctctctgta ctgactgaaa 128820 actccagcac acacctaaag ttactgatgc atcccaccac tcaaagaacg gcccttctat 128880 tccctataag aataaacaaa atgacaatat ttacagagtt ggagtattcc aggcatgtcc 128940 catcacacta ggctcgacag cctaagtaaa atgtgcatgt tagcgctgat gggaacatag 129000 aggtcagctg ctcactgaga aacaggagaa aggagatgag ttagatcaat agaaaatgct 129060 tacattcatt ccagtaagga atgataaaag tttaaatgaa cattcacaat ttgctgactt 129120 acttcacaac acgtttacta aagcttagca aagtgataat atgcacagat ccttttattg 129180 tagcaggaaa ctttaaaact aatataatgc gataaatatt ttatccgtgt agcataaatt 129240 aaagggactc aattgcctgc atcttaatct cgattagtgc ctgttaatag caaaacacac 129300 acaattaatt gtactttaaa agcagatcag ttatcaaact cagccttaga ataaaaattt 129360 tgatcttcaa atttgtttat gtagttaata tcattattgt tagttttggt gccagggata 129420 taacccaggg gtacacagta tgtgctaagc aatggcttag cccctagcat gtacattttt 129480 actatggttg aggaaccatt aaagctttag catcaatgaa ttaaatgcat tgctattaga 129540 aattagagaa atcttaaagc attaaatatc aaaattgtgt gaacatcaat cataaacaaa 129600 tgctaactaa gttacttttt aatggaaaat gaccatgttt ctagagaaaa ggacttacgt 129660 ggcatgggtt tttataattt tataaatttt caaatatcta acctaatatc tagattcttt 129720 tacatttaac agattttaat ttatatttag atggagaata tgaaaaacag ttggtcttgc 129780 agaaaggtgt gtggaaacct gaaatagcga tttcatgtaa gtataaatat ttctccttcc 129840 tggtaggcca cattagataa ataggtcaga gtcatatccg caaacccact gtactctgac 129900 ctatgcaatt cattggctta ttgtgcacag ttaggtgatt tactatccac aaagatatat 129960 gtcataagca tggcccattt atagattgtt agctgactgt gctatataaa gtttaaattt 130020 ttacagcctc tcctcattag tctgtcaaca tcactgctag tcacatctgg aaatccttca 130080 tatttaaaat gctgctcaat tcctggtggc agaaaagtgt tccagtattc taatggtcat 130140 ttttgtcacg ggcaatacat atttacaatt actttttact ccttgacatg gctcgatcac 130200 ttctctcatt tttgaaaatg acttaaaatg taagctggaa tggtctgcac ctgtctacct 130260 gctacatttt ccaaggcgtg atagtgttca atggaaatgg aatcagtcca gctggtaact 130320 cacacagctg tgcaggtgtg ttttggggat gatattgggg caccaaacaa acaaaaaaac 130380 gaacaaacaa gatgagccct ggggctccag atgaaatagt tttgcagcat catcaaacag 130440 actcctttaa gggaattgga ttttcatttt atagattatt atttttccta ggagcaaatg 130500 gctgtgaaaa atttaacaat tcttcatacc actgccttac taaggattaa cattgagaaa 130560 tataaattgt ttttgtaaat ataaataacc atcaacagtg aaaggaagga agagtgcttt 130620 tatatgacta taaagacagt tgggatatga tggatgccta aacgttttca aggaaatgca 130680 ccaaagttat ggggtaagat aaaaaataac tgcaaaagtt atttttaaga ctgttctagt 130740 cttgatgggg tggacacatt tttgagagca tcaaagacta aacactgagt tgataacatg 130800 actgaatgtt ttttgttttt tgttttttgt ttttgttttt gttttaaata aatgtcacaa 130860 tatggcgaca agattaaaag tgaagagtat gcgagagtag agagtcaaca aagtcatagt 130920 gacaaaggag aggtggctaa ttggtgagca ggtaaggttt ctctctggag gagaagctgc 130980 tggagtttgt cactttgtta ctctacagtg ttgcctggag ttcgatactt cattactcta 131040 tagtggggtg aagaagttca ccttcttatt ttcatttcct tccctcaatg atttcttcag 131100 agctagctct taccagctag aaattcttca aacgacactc gtgccttcct tcacacaggt 131160 tgaactattt gtctctaatg ccctaaagta ctggtgttca atcttccagg cacttccaat 131220 gatctgaaat ctgacctgct taggtcagct ggctctgaga ttatggtatt ctagtcctca 131280 aaccaacctg ttggctcgtt ggttttgtac caaacacact gacttacata gctcaaaata 131340 ccactggcct tttaaaaatg gcatatcaca ttccagggga ggatcaaaac tgctggctgg 131400 tgatatttgt caagtctctc aaagttgcac tttccaggat tttcaattca ctgaattctt 131460 agacagacat gtttatgtga aagaattctt tatatatttt ttctcctctt tgagtgggca 131520 aatgaaaatc ttgacctctg ggttccttat tttatttgac tctctgtagt atttaaatct 131580 taaaattttc cttaaaataa tctaagtatg gatattaatc catgatatta acgatcgatc 131640 cttgtttaca gggtgccttt ccctgctcct accaggcgat ttcatatttt caaggatcag 131700 ttcttgaaag aggatgtagc cctcgctctg ccaatggctc tggctcagcc tcatgcatct 131760 gcctttgcta tagtctcacc ggaacattga catagattga ttttgccaat gtgatcagtt 131820 gagttctaca cagtttaaaa atgtcatgtt ctggcttagt gtttagtggt gttctttgtt 131880 catttatcgt ttactatctt tagttttttt agtgtatact cattttttcc cctactaaaa 131940 cccatagcca ataatagaca ttccataagt acaagtaaat ttcctgaaaa ttttctgaag 132000 tctgactgga gacattaggt tacaaaatta cacaatttca agtttcttat atcaaatcta 132060 atcttgtatc acatttcttt ccaaaatttc catttttaca attttgctaa aacagcaaat 132120 taatatatta aatatggact aatttaatta atattctagg tgataaaata ttaaaatatt 132180 tggctatttt ctcatttatc tcctggtcac tattttgatt atgtaatgct tatccttata 132240 aattgatttg ccaagttcca tttgataaat aatgtgttct aacatctata tttaattttt 132300 taatgttaag gattaagttt ggggtctcac acatactgga caagtgctct accattgaac 132360 ctattttaac ttttaaaaca gtgtgttctt atttcaaaaa tattttctgc cattacaaac 132420 taaagaattt agaaacaaat caataaaatg ggaaaaactg cacaactaaa ttgttagtac 132480 taatgcttat tgtgcaatgt tttaaagtta tgttatttcc ttatggtttt tattttagat 132540 ctacataatg aacattctct actttattaa aaggagaaaa ataattctga ctttaaacaa 132600 attataacaa gaaaatagaa attataattg catatagcag actctaccaa ttctaacact 132660 agttttattc attttttttt taggggaaac aaacatttgt atctttttgg gatttgtgct 132720 attgtatcct cagcaacttt gtacagaatt aaatgttatt tgatatgtta cattcaatgg 132780 ccctgtaata tctttttgtt tacatagatt atgatttaac atagtatatg taaactgttt 132840 taagtttcat cgggttgcaa tgttttttcc tacataggaa tcttttggta gaagtgacag 132900 ttgaaggtcc agattattat taattaaaat gattggatgg atagtccaaa cttatcagcc 132960 agacgctgat ttgttagaac tgtaattcca aatctgtacc acaaacagca agagagaaca 133020 gttagctggt ttgttttagg agattacagc atcggaagtc caaccttggg ccaactactt 133080 ttactgcttg cttcattcct gccattttct ggtgcaaatg ttgggctcta ggctgcaaca 133140 ttttcccaag acattgcact ttgtttaaat gagcctgacc cagtttctat tgcttataga 133200 aacactttgg aattgatcgt tttatttata aaattgtcca taagctccta agttttgcat 133260 ccatcttggt tcctcttgta attaaaatga gtaaaagcct taatgcttag cacagatggt 133320 ggctctaaat atgcattcac ttctccacat catgttattt atgctgcttc tttaaatata 133380 atggtaatta gctaattaca acattagcat atcaacatat gcccacacta ctccttattg 133440 tgggagaagg gtatggatga cgaaaatcca tccttaatac aattttaatc atgtcatcag 133500 caacaaaaaa agactgaatt gatattcagt cttccttgtg tattttagtc atcataagca 133560 agccaaaggc aaccatcaca agatgaatcg tgttcacctc taggttcatt tgcctaaagc 133620 caaacttccc tactccatat ctgtgtgtat ttggaggcaa ggcctttaaa atagttggat 133680 cacacggtta gacacaatct aacttttctc catctaagtg gaaatttagg catcaaagca 133740 agcactgtga attcaggatc acagaagaaa caaacatgtc agagcacaga gcatgaaacc 133800 agcaagccaa gcagagaagc atcacaagga accatacctg tcaatatctc aaagcctgat 133860 ctcatgcaaa ctatattcct atagtttaaa ccacccagca ttcagtgtag tgttacatag 133920 gcccaaagca tctaaaataa aaccaactct atttgagaag tataattaca agtacaacag 133980 aacccctaat ggcatttgag agacaaaggt gactaagcag cgtctaatga agggcatgag 134040 catcacttac atgtgtgcag cagaggacgt gcaatgcagg agggaccctt ctgggaaata 134100 actagccatc tcctctcagg aagattaggt tcattaaaat gctgtaccta attatcactt 134160 ttgctttctg ggagtatcat aaacaaatgc tttcccaagg agaaggaaaa atttatggta 134220 cacttgaacc caaaggttgc aatgggagaa tatgggtcat ttaaaaaaac ccaacagatt 134280 taaatctatg taaggttttc caagaaggta cttttttggt ggcatttcct ttaaaaggtg 134340 tcttgtatat ctagtgtaaa ataaatgata gtaatagcac aaatgaatca ccggccgtgt 134400 tgctaagaaa gttcaacttg gatagagaat gcagtctttt caagaaagag ttctggacta 134460 agtagatgct tacaagtcaa agcaaggagc atgagccata agccgaattg catacaagaa 134520 actgactcaa atgaaccaga gacataaaca aaagagccag ctacaaaaac atactgcaaa 134580 caaaacagaa tcaatgtcca gttttgcata gagttaggcc tatatggtac taaagaagga 134640 caggtgatat taaaaaaaaa caacaacaaa aaacagaaac aaacaaacaa acagaaagtc 134700 cgtagatact gcattaaagc tagaggcctg ttatcatggg agtaccagag gagctgaaca 134760 agagtttttt ttattgctca taggagaaaa cttgaaacca ggatctattg taagttgaaa 134820 tccacatctc ttagaaaatt ctagggtctg atctgagaac aaggagaaaa caggtagttg 134880 tgaagtctaa aatgattctt atttacgtta tactccctta taatgtggat tctgagtaaa 134940 caaagcagta atttcaagct gagctctggt tttccaatag cacactcatt tacttgcaaa 135000 acatgacttg attgaacacc actggccagc tgttgtgtgc caactgcagg ggcagataag 135060 ctccggtcta catgtttctt cttgtatgta tagtctgtat cattctcacc aataacctca 135120 cccagaatct ttcatcaaat tgtgcatatg tgtgtgcacc tgtgttgggt gcatgagtgt 135180 gtgtgtgtgc atgtgtgtgt gtgtgtatgt gcatgtggta tgcatgagtc tgtatgtgtg 135240 tgcatgtgtg cacctgtgtg agtgcacaag tatgtgcaca tgtatgggta tgtctgtatg 135300 tgcatgtgta tgtgtgtgca tgtgtgtgtg tgtgtgtgtg tgtgagtgtg tgtgtatatg 135360 tgtgtgtgcg ttgtaacatt tttctagcca acatcactgc attctaggaa tgacagcatt 135420 tttcctcaga gacttaacaa gttgttaaaa aaaaaaaagc tccttgtaaa tatgaacaga 135480 ttacttttct aaacctagaa acttgccaat ataaaataca aggcttaaat ttattcaacc 135540 aatttccctc atgcttttta atagaaacca ctttaagagt ctgagtccag ccaccaggaa 135600 cccacagatg tggggatggg ggtgtctgtt agtcccagct ctttcttacc tctgcataga 135660 cccacccata cagagggtcc ttttctcaca tcacctcagg tcccaggtcc caggacctct 135720 gtgcggtttc tgttcccagt ttttcaatca ttgttccttt cttatacgca agggtctcca 135780 tccctctact catttagatg tctcaactac aaggtcacat ttctacctcc tttttctctt 135840 caagcccctc tctcctatca tctctttatg cggtgttctt tttctttaag ggcctttgat 135900 agtcctttgt gcattttttt ctaactttat tactagactg aaggcaacat atgggcatga 135960 atttccttgt aatttccatc tttcaacacc ttcggacacc aactagaggg ctttgtaaaa 136020 aaaaaaattt aacttggatg tcactttttg acatcttggc atgaaaggat agagaggagt 136080 tatgctggca agggctgatt tccttttcgg agtcagggct aaccagtggt tctaccacca 136140 cacagacatg agtgttctag aatacagaag ctatggcaag gctgcctgag ttcaagtttg 136200 tgctctgcca cttatctgtg taacatttgg caaggcaatc tagtctcata gccttcattt 136260 cttcccttgt caaattatca atattacata gttcttacat tcctgaagta ctgcttagca 136320 aagtaagtac tacctctcta taataagttg acctctaggt acgtagataa aagagaagag 136380 ttacaagcac aagtggagcc actttgtaga tcatctggat ttttcagaca cgtgtgcacc 136440 aagagtaagt ctctttctac agcctaccct aagccagaga aacacaaacg gagctgtaaa 136500 ttccgcttaa ttgacatttc agaatttcaa agggaagtaa ttgcgtccct gagcttctct 136560 gcactgatcc agagtgggac acatctcagc ccatggattg ctgtggttct ctttctttcc 136620 ctgcactctt tctccccctc ccactcttcc aagtcagatc aggccttctt gctgaagggg 136680 aatggaaagg agtacctggc ggatttcatc ttcttcacct aacctggagg gagaggacaa 136740 cttggataga acttggcatg cctggtttta ctgccgtggc ccccgaggac tacccagatc 136800 tccgctgtcc acagagaatg gaaattaaat tcaggctaac tttcatcatc aggaacactc 136860 agataatgtg ttctgatcat catgtgcctg tgtgtgtgtc aattttgagc aactctccac 136920 gagagaaggc ttctcagtgg aatggagtcc tgagtttctg gtccttgggt tgtgtccttc 136980 tgtctgtcca cttgctcctg atctttttgg atgggaaggc agattgtttg ctcttctccc 137040 cagtgccttc ttggatactg tataattaat taggcctcca atcatgcctt cccagcctcc 137100 acggatggag aaaccctctc cgccatgcct taaagaggaa ttgctgtaat aaatgagtct 137160 cctgatagca aatttctcag caagggggaa tcgcgtaaat ggagacatag tattgacagc 137220 aaagtccaat gtgttatttt taccagaacg aactctccgg ttcaagcctt tgaaagagac 137280 atttgaaaac caaaaacaaa caatgtaatg gagcgaggaa aaaagccaca gaagtgagtg 137340 gcagggagtt taaaagagca gatgccactg ccaggtctat gggacataac cagccacttg 137400 tgctgggtct tggcagttta taatgctacc tcatcttctc cgcgaaattg ttttcccgta 137460 aatctctgtg gccatccatt cctgtctaca cattatgttc ctaaaataga caccatctaa 137520 aaatcacttc aaggagcttt gtggaggaag gcctaaattg caacactcct ccagcgaaga 137580 tagatgcagt gtttgatggc attaccagtc ggtagccagg aaggggagtt tgtgaggagt 137640 ttttccacca cagttaatct gtttctggaa ggaaagggaa gtgtcagact tcccgaggag 137700 gcaaacgtgt gtggaagctc tcatttgcat cacccccggc ctgtcaggta ttgcagcaaa 137760 agggagaggt gagctaccct ggctctcctt gggcaggagg gacagaatca ggaagcatca 137820 acctcagcat ggaattttcc tattcctgtt tggcatcctc ctcttgggat gatttacagc 137880 gcgggttgga gaaacacgct ctgccactcc actagcgcac cagatagaca gtgcagacct 137940 gcagatccat acccgaggag aagccacatt tcctacgtgt gatagcaaca gcgtttggca 138000 atttgcgact ttgctactgc agcttagaaa atatttagtc acatgcacat ctgaacagaa 138060 agacacccag gcttgactca gtcatttccg tcagacacac gaaagaaaaa gcgtctctgc 138120 tcacaagctt atttggactg ctttgttgaa aggaggggcg gcagacactt tgtagatgtg 138180 gcaagagggc tttatatcca gacctcaaac aggtaggaga gaaggaagcc aggagaggta 138240 aggaaggggc gtggaaaagc ctcacagcca cctcgaagaa aacagttttt ttgccctgtt 138300 cagaaagcaa gaggttccac agtggttttg tgtcaatgga gcacatctgc agtatcattg 138360 ccgttggtga cctctgtcta attaaaagta agtcagtcct tcccacccgg cattgtctga 138420 aacccgggac tctttatcac tttgctaaag ttcatttgca agtgtagtta aggaagagtc 138480 aggggggaaa cagcatctgt cccttctggt cctggggagg aggcactcct ttccaagagt 138540 caagcctctg cccaaagaag ctgcctcccc tgcaatgcta ggatccagga gcagccccgc 138600 tgccttcttg cttcctctgt gaggtctaat ttttgcatca tctttaggag cgatatgacc 138660 tctattcaca gccatcgaat ccagttccaa agcaccaatg acagaggggg cttcaagaca 138720 agaccttgcc taggaggatg caggcaagca aaggcaagag ctggcccgat gccaagttat 138780 tttaggccaa agaatctcat ccttctatca aaatgctgaa ctgcaaaacg aacctgattt 138840 cagttcatgg aaggttgaga ggaggaggag ggggagggga ggaggaggaa gagaggagga 138900 ggggaggagg agggaggagg aggaggggag gaggaggggg acagttggtc cgaattcaca 138960 tgcaaaaata gacttcctgt tctgccccaa ctcttatttc cgtgggctct tctccccaag 139020 gatttaccag gtaagaattc accaccaaag aagatcacaa tgagataatc agatggctta 139080 cctgataaaa aggaaaatta tccatctgca gtgaggagca acatctcccc acgacgagtc 139140 cgcaccttcc gttgcaacga ttcagattcc ttcttgcaaa aggtgaccaa gtgcttcaca 139200 agggctgcag cctcataggg gcagaacaca cgtacacaaa cacacgcaca cacacacaca 139260 catgcaccag agacctctgc agtatcctct cggcttcatc ctcgcctcac tctatggtac 139320 ctaatacaaa tcagcaaata gcttgtttta aaaaaaaaag aaagaaaaaa aagcggagac 139380 agcacctaac gttacagtgc catctagtgg ctacatcgta aataggttct cacagcctgg 139440 atttctgtgt tctttctcaa ccgcttcctt ctggttcctt tttctttttt cctctttatt 139500 ttggttttat tacttcctca gatgcctttt tttcattccc ctttgctctg cctatcatgg 139560 aactattgac ttaaagatta aaacaatcag aactggagag cgttgctttt aagttaaaaa 139620 aaaaaaggtg ctaattttgt ttgtaaatgt tactttattt tctctattaa aaaaaaaaac 139680 tcattgttac ttttacagat tacggaaccc atgaatgaaa tttgcttatt tctactgtct 139740 ggagaaaagt gagtagtctt ttactacgta gtcgtgactt tacatgagga attttgtgga 139800 ttctttcttc tctaacaccg tgttcacggt gcttttcata ctatagtgag tggctctgaa 139860 ggaggcagat gcgagtttaa ttttaaactc agtatcgatg agtgtgtttt gaagattata 139920 tccccctatc tttagtattg atgttaaata ggattatttt tatacccatt tccatggttt 139980 caccatcttt tattgtaata tatctatttg tctcccagat atgactagcc attgaattgt 140040 cacactatgt tttagagaac aaacgtaagt attaaatatt attggtgtcc actaggtctt 140100 cccaaaacaa tgaggagccc atactgaagt ctggggagct acaggaactg aactttctaa 140160 gccatatatt ataatttaaa gcatcattag tctttcacat ttggtcatac ataaacttat 140220 ttaccctggg tgtgtttctc ttgtcactta gcacacttaa tgctgatgaa agtcaccata 140280 catgctttgc tattaaaaaa aaaaaaaaaa ccaatatccc ttagacttta atttgtctat 140340 tccatactac aggacaggga ggcatatact gttaatattc ctctagcaat tctcattgta 140400 tgttgagaat aatgagacat tctgaacctt attgagactt ttctagacca catagtttgt 140460 gaagcaaaac aaaccaacca accaacaaat aaataataag aataaggata aggcccaccc 140520 tttcagaatt cattattttt tggaaaatag taaatatttt acctctttcc attctagaat 140580 cctggagatg taattttcat tgtttcttta taaagaaatt ttacaagtcc ttgtttatgg 140640 gttcatgggt ccatctcctg ggcccctttc ttagtttctg aaaggaagca attgaccaaa 140700 attgagctgg aagtatatag ctcatttggt agaacactta gtagacatgc accaaaaaac 140760 caaaacaaaa caaaacaaaa aacaaaaaaa cccaaaacca aaaacaaaca aacacacaca 140820 cacacacaca cacacacaca gattttcagc cttgtagact gcttgtacaa taaaaacttc 140880 agaacttgga atgctgaggt agactgatca caaatatgag ttcaaagtta ttatggggtt 140940 agaaattcca tgccaacctc agcctcagac atagtcacag gctcagcctc agcaactacc 141000 acagccatgg tcacagtcag agccacagcc acaaacacaa ccacagtcac aggcacagct 141060 tcagacacag acacagagag agccacagtc agggcctcag ccacagcatt agccacaacc 141120 tcagccacag ccacagctac aggtagagcc tcaggcacag acagacacaa acacacaaag 141180 acgcagccat agctgtcaaa gtcacaatca cagtctcagc ctcagacaca gactcagcca 141240 cagcttcaga cacagacata gtcataaaca cagagaaagt cacagtcatg gacacagcta 141300 caaccacatc ctcagcttca gccacagcca tagctatagc tacagcctca gacacagaca 141360 cagacagaca cagacagaca catacacaga cacagccata gctgtggcct cagaaacaga 141420 ctcagacaca gccacaacca ctgccacagc cattgtcaca gccactgcca cagccactgc 141480 cacagccact gccacaaaca ctgctatagc cacagccact gcaataggca ctgccacagc 141540 cactgctata gccacagcca ctgcaatagg cactgccaca gccatagcca ctgctacagc 141600 cacagccact gctacagcca cagccactgc tacagccaca gccactgcta cagccactgc 141660 cacagccact gctacagcca ctgccacagc cactgccaca accactgcta tagccacagc 141720 cactgcaata ggcactgcca cagccacagc cactgctaca gccacagcca ctaccacagc 141780 cactgccata gctgcagcca ctgctatagc cactgccaca accactgcca cagccactgc 141840 tacagccact gccacagcca cagccacagc cactgccaca gccactgcta cagccacagc 141900 cactgctaca gccactgcca tagccacagc cactgctata ggcactgcca cagccacagc 141960 cactgctaca ggcactgcca cagccacttc cactgccaca gccacagtca aagtcacaaa 142020 cacagacatg gccacagtct gagcttcagt ccgcactaca taatgagaag ctgtcttctt 142080 aaaaaattaa gttaacttcc tgttccatct ccaaaatgca caataatttg tagctcttca 142140 ctgtctgaaa aaagtgttgc tccttctctg gttcaggctg agtaacactg gaagaagctg 142200 gagtgaccaa cacttggtaa ctagttacta gaaagtttga aatgaaaagg cagaagggaa 142260 catttgaact aagaagtagt tttatattta tattatgatt ctaagaccat atactccata 142320 tgaacagtac ttaggattta aatatatgca cataaaaata agaacatcca aaagacatac 142380 tttactactt actaatagca tattccagaa gtcaatgttg tgcatttttt cttaataata 142440 atatcaacat ctctccttcc ttattgccag agtgcacttg gtcccttgtc tatagaggac 142500 caggagggcg tgggtggtgt gttcccagct gaaccagtct aaagaactat gacatgactg 142560 ccatctatgg aactaacctt ctcttttctc tcaccatagc attagaagca ggtagggcag 142620 gcaggatgcc tacaggaaat gtcacagcta atgaagaatg agggaaccat ccaaagccag 142680 tgcactccct gggttcctaa tgatatcaca ggtacaaggc agaatctcag aagatctgga 142740 acgtccctga tttgagtata caagacagcc cctaaaaagt ctctggacca atctcttttg 142800 atatccccgt gtactcaaaa ccagttgatt tatggagaga ggagtttaag ccctgaagat 142860 atcaaatatt ggttatatca tgggtgtcca actctgaatt tactcacttc aaaagtacct 142920 gctaataaag gcattttccc aggcttaatt aacaccatta agccaagcaa atgaactctt 142980 actttgagaa gtttccatct cacaatgaga gtcagtgaga aagggagagt attttcaatg 143040 catgcacccc tcttccttcg gtttgcctgt ttctttcatg acttctgcat cttaacaaac 143100 atccagccat ctgcacaagg caaagtggac cagtgtctag gtcaaacatc tttttctcta 143160 atgctttccc tgtgttttca gtgaataggc tccttttgtt aattgtaaaa taaatttatg 143220 ttttctttta tggaatatgg tcacggatta tattgaaaat gttaatcgtg agagaataaa 143280 tgtttctttg cagactgttt ctgaagaagg ttaacattcc attcactgta caagagtgct 143340 ttttaatgaa taaaaaatat tcattaaata tagcttgtca tttagtagca gacacgtgat 143400 tcatcagagt ggtaacaaca ccaactgctt taatttttct tcatctaaga cctgccatga 143460 aggaaaagac aagattttta aaaattagac ccttaaaact atgtatttaa attttaaatg 143520 ttcacttttt aaacataaaa atgtaaacta aaaagaaccg taaaacttta tgctgctctc 143580 acccttgtgt ttgctggcct ctctggactt ttgctaaagg tctcccattt ctatctgtct 143640 accttctaat aatgaactgc agttgggctg gcatattata tcccatatac cttttgtggt 143700 atcttagtta atgaagaaaa gtttttattt ttcacttttc cctggcttat ttccatcaac 143760 aaagactgaa ggggccattt ccttatttct gggagacccc atgtgatctc atctcagaaa 143820 agagaagaat gttatttctt ggctgtctct acttccctag atggtgggtg caggaacttg 143880 acaggtaagc tgtgggctgt gcctcttctg taagcggttc caacaagaga agaaaatgag 143940 aacacaaaat gtcttgtcat tgcttttgcc actctgtctc tgtcaggagg acacagccat 144000 ctctttgcca ttactctgtg gggcatgggc tctgcacaga caggatggtc tccagttgag 144060 ctgaggtctg aaccccgttt gtgataattc acctaaatgg cacggtaggc gttccctcat 144120 gctcctggaa ctctggctcc tgcctaagtt actgcccccc acaaccccca caagagaagc 144180 atggtcagta gtcacgtagg caatggccca agcttctgac cttcaagcta aactcctccc 144240 ctgttaccta gcaatagtga ggaccataaa aagggctgtt tagcccctgc ttgctctctt 144300 acctcttact tctcactctc ttacccctca ctctcacccc ctctctcctc tctctttgtc 144360 ttctcttctc tttcctttct ctttgccttc tcctctcctc tcctctcctc tcctctcctc 144420 tcctctcctc tcctctcctc tcctctcctc tcctctcctc tctccctctt actctctttc 144480 tctctagcct tctctctctc tcccttctct ctttctccct gcctttctat aataaagctt 144540 taaaaccata gagagtctct gctcatcaag atccgcttca tgcactctca caggtgttgg 144600 gaacctcttc cctcgtcccg ctcttctata accctggtgg ctttagcaag gtagctcctg 144660 gatccccagg tagggctgcc ccttggccac ccgctgaaga gtgggtcaga ggcttgaatg 144720 cccacccagg gatgagtgga aagtgtatgg cagctctccc atgcctgaca gaccagagaa 144780 taggtaaaac tctggcgggg tgtgagtccc ccccttccct agggaccccc tttttagttc 144840 ccaacattac tccatcactt gctggaaagc attagctgct tagtggccaa agaagggaga 144900 ttacaagaga tgttacctct gttggtagaa tgtgggtatt aaagaataaa tgtgggattc 144960 aagtggaaaa gatagcctag gttctttcta cctatcagtt ttaagataag caagaggatc 145020 tcttgtgatt agcatcttga atgattcaaa tgttctcaag accagaaggc attaaaattc 145080 cacagtgaaa ttcgtaaaat ctcctaacat ggaaaaaata tcctttgtta atttcaattt 145140 tagaatgtta attgtcatgc attgtgacaa ccactgcttg aatatatttt ttgataatca 145200 ttaaggaatt gtggaactgg aaagttttct cagaccatcc agaagacgat tattattttg 145260 gataacagaa atgtgacatc cagagagata gtatgtcttg ttcaaggcta tacagacagt 145320 ttggaattgt aaaagttcat tcaaactttc ttccccgttt aactatgaag aaaatgaata 145380 ttgagcaatg acatcggcac acaagaagtg aaatggaagt gaggggaggg tttctggata 145440 taccacgatt gattttccct aatgatttga ctaatatgaa tgaaatagga ggatataata 145500 gaagctgtct gtttaaaaag gtgatggacc aggagggact tccagtggag ggaggggaac 145560 accaacctat tcacaaaacc tttggcccca aatttgtcct acctataata tgtgcaggga 145620 taatatatgg ggcagagatt caggtacaag ttaaccaatg acttccccaa ctttagaaga 145680 cccccgcccc catgggagat ctaaatcctg acactcttag tgatattctg ctatgcttgc 145740 aaacaagaca ctagcataac tgtccagcag ccagtggaaa cagatacaga gtcccacagc 145800 caaacattag gcagaactct gggagacttg gggaaggatc gaaagagtca gaggggtcaa 145860 gaacaccaca agaagctcta cagaggcaac taacttgagc ccatggggct cacagagact 145920 aaaccaccaa ccaaagagca tgcagaggct ggatatggac cccttagaca tttgtagcag 145980 atgtacagct tggtcttcat gtgggcctct taaaaatttg actgggggtt gtctctgcct 146040 ctgttacctg cttttgatgc cattccccta gctgggctgc cttgtctggc ctcaatggga 146100 gagaatacat ttcgacctgc tatgatttga tatgccaggt agattggtac ccatgggggt 146160 tctctgagga gaaggtgagg tggcactgag ggagcagtat gtgagggcag gcctagcagt 146220 atgtgagggc aggcctaggg agagaggagg tagaagggtt acatcaggat gtaaagtaaa 146280 ttaaaagaaa aggtgaaagg ctaaaccaat attgggttaa gcactgatca ccctcatgta 146340 tagctttgca gacagttctt aaaaattgac cacaaacttc tcaaactcaa ggacatgaga 146400 gtacaacact catgactttc attcatgtcc aaggagagac ctggaagaaa attgtcccaa 146460 ggttctaaaa tttcattaca atctgaagta aaatctgaaa acacatttta tgtttcctta 146520 gttaataaat catagcctcg aaggaaaaca aagaaacctt ttctttcttt ctttctttct 146580 ttctttcttt ctttctttct ttctttcttt ctttctttct ttctagataa agtcatgatc 146640 ttgtcttgtg taccttcaaa gacccagacc taaatggtcc ttctgtcttg cctttcaaat 146700 agtcaggact gatggcatgt aataagtaat aagggctgga aagtaaagta gtatgctgct 146760 catgcctaca ttgtatacct cactggcaaa cagatcaagg actaggcctt agccttggag 146820 gcaagatcta ggcatattac agtatttcaa ttaatttgtc tggatctact cttacagggg 146880 gatgaagaga gaatgaaact ataacaagaa acaaagaagg tacatggaaa gtcataaagg 146940 atttggtaac tatgctggat tctcttctgt gctcatacat actggctttt atgtcaggaa 147000 gtcattgaaa tatattgcct gggttcctcc ctcatccctt tcactcaaca atcctcctcc 147060 tttgcagagg taagccaact aaaactgtga caaaaatatc atcaattact tattggattt 147120 caaagagcaa ttttccattt gactatattt tgaagtcaat cacagcactt gcctatatat 147180 gcaagagatc tagcacactt taagtttaca gattattttt gatattaaag gaaattgctg 147240 atatttatga agacaactca cttttataaa ataaaactga actttgccat gacttaggat 147300 aagccaataa tgtgtaggca aatatgtaat tcctattccc ctgaaggctt attggtgaca 147360 tctttttctt ttcctgttta aaaggaaaaa aatctactga ccttcctagg aacctctcac 147420 agtcctcaca ctgtgtgtgg gtgtcattac agccaagtgc catcttattt cacatggctt 147480 agtgatcatt gctgaagaag tggaggaaag agtgtgagag acagaggaac agcaagcttt 147540 ctgtgagact gggtctccta gaaatgccag agagattaca cccatagagt ctcatcaaca 147600 tggctgccta aataagacct gaacaatgac aacaccaatg gccatactaa catgcaactg 147660 gggaagataa ggaggttcac actagaggaa gaactatgga caatagggaa atgataagaa 147720 ctggagaaat ggttttccct gaggaagaac tccccaattg ttatctgcta taaagtggtc 147780 agccctggca taagatgcat acaggtaaca ctatatggac tgaccaggtt tacaatatca 147840 cagtgaatgc tatgtgtttc atatatacaa gctatctatc tatctatcta tctatctatc 147900 tatctatcta tctatctatc tacaattaaa taacaaagat gccatgaatt tggatgaaag 147960 caaagagggt tacatgggaa gagttgggga gagagaaagg gggtcatgtt ctaattgtaa 148020 cttagaaaac aattttaatt actataaaaa gcattcatag gtttagcata attcatagaa 148080 acaagctctc tatgataaat gattctactt aacaccttga tacttggtac catcctgtgg 148140 taagataggt tctcagaaaa aaatgtattg atacttaaat atttatttct ctttccaggt 148200 caaaatttga tagtgatttc aaatatatgg aaattattgc taaaacttag tataggctga 148260 gtatttgaac actcacagga aattcatgac attgatattt ttgccatcat tttataggtt 148320 agaataccaa aaaccaaaac tatttatcat ttttgccaag gagataaaat gtagcttgga 148380 aaatagcagc ctatcttcaa agtcgggtcc ttgttttata gaaatctctt tctagcacca 148440 cattattatt atgctattgt caagtctctg ggatccaagg ggaaaatagg agatggtgca 148500 gctcttcttc actggtctgg gaaagatcac aatgtgctta catagacacc atggatgaaa 148560 catatttcta aatgtaccca aggaaagggg gttttgaggt acaaggcagg ctggcagcca 148620 cagttccaac aaatgtggta ttgggtatgt ggccaagaag gaaagtagca aatgacacct 148680 ctttttactt gaccctaagt ctcagatctc ctactgcagg gtggtggact gtaaggtatg 148740 gttgagccaa aggcttgatg ccctggagac cctgaagatt tagtaggagc ttcgcctgct 148800 ctcagcacca atcccctgtc atatagccat agccccctat agatttgtgg ttatcagtag 148860 ctgaagggca atgcccaagc ccttccacat atagatgaag catctctaac atctcggacc 148920 aagaggcatg actacagtca tgtaagctca aaacagagtt ctctatgcca atgaggtacc 148980 tagaggtcga gagggcattc caataagctt cctttcccat acatttctcc ctgcaaaagg 149040 tatatcatct catgccaacc ctgagaagtg gggtatggtt ctacagatcc attttccacc 149100 atgacaataa taaactgttt gggaccatgg aatgcctctt tttttattgt gatcaacagt 149160 gggaagacat ggagaaggcc ttcgcctaca gagtcacagt ctagtctctg aaagaaggca 149220 tctttgcatt ctcagccacg atcaccacca agcctgccac tatcaagcca aagacaattt 149280 ctgcagggac tagctggagc tcctccccca tgtccaagat cctgagaacc cacagttctg 149340 gggagcaccg aaccagtacg gagtcaaact cccccatcca gtctccacaa gtggccgtgc 149400 tcagtggtgg gacagacttg tgatgacaca accctacatc ctacaacatg tgaaaggata 149460 tgactgtttg gaaattctct tgccaaatga acacatcaac taaatttcag aggagcattc 149520 aggggagaag aatctctcag tctgtcagta ccttagtatc cacaagtcga catttgttga 149580 acataaaaaa atgaaaagag cagaatttct gagtgtgaga ggttgacaat gaggcttctg 149640 acaaagcttc atgtttcaaa tataatattc aatgtcatgt ttttcttttt ctcagcacat 149700 tttttgaaaa ggcaagtgct ttctggctct gctggatatt tgtgaagaca cggatcacat 149760 gagaacataa aactttgtaa gctttaaagc cttgcttctc gtccgagtgt ggcagtggaa 149820 caacagcatc tccatctttg aggggcttgt taaaattttg gaccatttcc tttgtcccac 149880 aacctgccag atcagaaagg acgttttgac gagctgccca tgtgattcca gtagacactg 149940 tttaaaagtg ttgctgtaga gtgccgctat aacaggaact tgagaactta acataactga 150000 tgttatgacg caagtaccat tccctaatgc tcctgcaatc ttttcatatc acctcaagtt 150060 gtagggacag ccaaccataa aattatttct gtttctacat cataactgta atttttctac 150120 cgttatggat tgtactataa atatctaata tgcaggatag tcttaggcaa tcgctgtgca 150180 agggtcattt gtccccacca agggttcatg acccacagat tgtgaactac ccatttagac 150240 cctaaaagct cagcacatag acagtacaca acaaagacaa agatctgatc catcaaagtt 150300 catagttcta gaaccatctc taaatgcacc acctttggat ttttggcttc tgtagttctg 150360 ctttggctaa ctgttcttac taacacaatt ccggaggtgg tttcactctg agaaaggttc 150420 aggattatac aggatcatga atacccagtg ttgtctctac ccagctgata aagactttct 150480 attgtcttaa acccatgtcc atgcactctt ctctggtgga caacccacaa cattagctaa 150540 tactttcaca cctctcataa gagcttttat ttttaattaa attttaattt tgcatgcaaa 150600 ataatgtttt tattatgaca ttatatatat ttatccatat atgcataaat atatacatat 150660 atgtcattac atatacatat atataatgtc tatatatgta tataacaaat cattgttctt 150720 atttgtttac cccttactcc tctacccttc tccaacctct tctttttggt ctcctttctc 150780 ctcctaaata aacctccctt ctgatttcat gacccatgtg acctaacgtt tataaggcta 150840 cctatttttc tgtacccaga gcatgtgact aaacaatttg tcccttctca tcattttctg 150900 ggcactccac actccaatcc agagaagcta tctcctaatc tactcttgaa gtaacagttt 150960 gaaaattaga tcaccatgct ggctctttaa gtaaaaccta gccttcctat ttactgcaca 151020 ggtgcaggcc ataccagtca gaaaagggaa gagccccacc agataactga accctcctga 151080 taactaggtt tggagcccaa acacccaagc cactgacacc accaccctac tgcctgctcc 151140 cacttcttgc acttgcctct acgcaggtga ctctccagag cacaggtgca ggccaggcta 151200 atgagaatga gtaagaggcc catctgcact cagaaacctc ctatgccctt ggtttggatc 151260 cccaaggcac actctgtaga catcctttct gtgttttatc acccacagag ctcagttaat 151320 atttttaaca aaaccataga ggaaaaattt cctaacctta agaaggacat gtttctaaag 151380 gcagaaaaat ctcttaagac acaaatggat tgaattggaa aagaaagtcc ctggtcaact 151440 aataatcaaa acactgaaca tgcagaacaa agaaaaatat taaaagctgc aagagaaaaa 151500 aggccaaata acatgaaaag gtagaattat tagaattata tttaatttct taacagagac 151560 cctaaaagcc agaatagcct ggacatatgt cttacaggct ctgagagacc atagatacca 151620 tcctagactc gtctaacaag caaaacttaa aataaaaaga tttattttta tatgagtata 151680 ccactggtct cttcagattc accagaagaa ggcatcagat cacattacag atgtttgtga 151740 ggcaccatat ggttgctggg aattgaactt aggatctcgg tgctcttaat cactgagcca 151800 tctctccagc ccgccagcaa aactgttcat cctcatagat gggtaagaca agatactgca 151860 tgacaaagtc aaatttaaac aaaatctact cataaatcca ggcatatcga ggtacaaatg 151920 gaaatcaaca accctaggag gttaactaca cccatgaaga aataaataag ctcatacaaa 151980 aattagaggg aaacacacac acacacacac acacacacac acacactagc actaccataa 152040 acaacaacaa aataataaga attaacactt attaatcatt agtatctctc aatatcagtg 152100 gactcaattc ctcaaaaggc acaggctaac agaatgaata ccaaagcagg atttatccgt 152160 ttgttacata taagaagcac acctcatcat caaagctaga tattacctaa gagttgaggg 152220 tttggaaaaa gattttccaa gcaaatgtac ccaagaaaca agctgttgta tctgttgtaa 152280 tataagacaa atcgacttca aaacaaaaat taatcaagta gacagaggac acttcatatt 152340 taccacagga aaaccccacc aagatgatgt ctcaattcta aacatctatg cccctcaaag 152400 caaggacacc cacatttgta aaaccacaca tcaaaacaca tgtattaagt cgggcgtggt 152460 ggcgcacgcc tttaatccca gcacttggga ggcagaggca ggcagatttc tgagttcgag 152520 gccagcctgg tctacaaagt gagttccagg acagccaggg ctatacaaag aaaccctgtg 152580 ttgaagcccc cccccaaata tgtatttaca gtgggagaca tcaggtcatt cagacaaaaa 152640 cttaacagag aaataatgga gttaacagac taacagactt aacgtggact taacagttat 152700 ctacagaaca tttcacccaa ataaaaacaa tatacattct tctcagaacc ccatgaaact 152760 tctttttcaa aattgaccac agactctgtt acaaagcaag tctctacaga tccaagaaaa 152820 ctggaacaac tcccccatct catcagacca tcatagatta aagatgaatt ttatcaacaa 152880 cagaaagaac aaaaagctta aaaacttatg taaactgaac aactctctac tgaatgaccc 152940 ctgggtcaaa cagaaataaa ggaagatatt aaagactttc tagaactcaa tgaaaatgaa 153000 tgcacaacat acacaaacct atggcacaca atgaaagcag tgctaagcgg aaagttcata 153060 acactaagaa ccttcatata gaaattagag agatttaata ctagcaactt aacagcaccc 153120 ctaaaagctc tagaataaaa taagcaaata cacccaagag gagtagatgg cacgaaataa 153180 actcggggat gaaatcagta aaatagacac aaagagagca atacaaagaa ttaatgaaac 153240 aaagggttag ttctttgaga aaatcaacaa gacaaaatca acaagacaga caagccatta 153300 tccaaaccaa ctaaaaggca gagagagaga gagagagaga gagagagaga gagagagaga 153360 gagagaatat cttaacaaaa tcagaaaaga aaaggggggc atgataacag atactgagga 153420 aatacaaaga atcattaggt cgcacttcaa aaacttactc cacaaaatta gaaaacctaa 153480 aagaaatgga caactttctc aatagatacc acttatcaag atcagataaa caattaaaat 153540 agacctatga cctataagga aggaatcaca ggaagcagtc atttgaaaag gctcccaact 153600 cccctacctc acaaaaagga aaccctcaaa caagagctaa tatcaataat ccttaaatta 153660 ttccacaaaa tagaaataga aggaacatca ccaaattcat ttcatgaggc cacagtcacc 153720 atgataccca atctgcaaaa agactcaaca aggaaagaga attacagacc aatttttgcc 153780 catgaacatt ggtataaaaa tactcaagaa aatatctaca aactaaatcc aatatacata 153840 aaagatgtgt tcaacatgac cacataggac acatcacaga gattcaggga tggctctaca 153900 tatgaaaatc tgtcaatgta attcaccata caaacagtga aaaaataccc gacgtgatca 153960 tctcattaga tactacaaaa gcctttaaca aaacacaaca ctccttcatg atacaagact 154020 tagagagatc aaggatataa gggacatacc taaacatagc aaagacaata tacagtaggt 154080 ggatagccaa catcatgtta agtagagaga aactcaatgc aattttacaa aaatcaggga 154140 caagacaaga ctgtccatag tacttgacat tctagctaga gtaataagac aaccaaagga 154200 gatcaagagg aatacaattt ggaaaggact aagtcaatgt attattattt tcagatgata 154260 tagtagcata tacaagcagc ccataaaatt tttccaggaa actcatacag gtgataaata 154320 ccttcagcaa agcagctgga tacaagatta actaaaataa ataataaata aataaataaa 154380 taattcagta tccttataaa catcaaatgg gttgagaaaa aagaaatcaa ggaagcaaca 154440 cacttcatgg tagataaaga taatataaaa tatattgggg caactgtaac taagaaactg 154500 aaaagcttat atgataaaag ctttaggtct ttgaagaaag aaattgaaga tgtcagaaga 154560 ttaaaagttc tcttatgctc atggacctgt gagattaaca tagtaaaaaa aagcaatcta 154620 cagactcaat gcaaacccca tcaaaattct aaaaaaattt ctttacagac ctggaaagaa 154680 caattctcaa cttcaaatgg aaaaccaaaa aaccaaggat agctaaaaca atcctgtaca 154740 aaaaaagaac ttcctaaaac taccacaccc ctgattctaa gctctttgac agagctatca 154800 tcataaaaac acatggtata ggcataaata cagacaactt gatcagtgca atcgaatcaa 154860 agacccagat gtaaatccgc acacctgtgg acacctgatt ttttattaaa gaagacataa 154920 ttatacaatg gagaaataaa gcatcatcaa caaatggtgc tggtttaact ggatgttggc 154980 aagtagaaga ctgcaaatag atccatgtat attaccctgc acaaaactca aggccacatg 155040 aaccagagac accaacatca aaacattgca cctgatagaa aagaaaggaa tagccttgaa 155100 tgcattggca cagaagacaa cttcctgaag agaacatcaa tagtgcaggc attaagatgg 155160 acatttaata aatgtttcct catgacactg aaaagcttct gtaaggcaaa ggacaccatc 155220 aaaaggacaa aatattcaag gtacagaatg ggaaaagata tacactaact ccacacctga 155280 cagacagcta atttctaaaa tatgtaaaat caagcaagca agcaagcaag caaacaaaca 155340 aacaaaaaac cctcaagaat ctagacatca acaaacaatc caatttaaaa atggggtaca 155400 gctagttgtg gtggtgcaca cctttaatcc cagcactcag aggcagaggc aggcagatct 155460 ctgagtgagg ccagactggt ctatagagat atgtccagga aagacagaga aactctgtct 155520 taaagctcct taagacccaa ctataccaat cctgagcata tacccacaga acagtccaca 155580 aggacagttg ctcaactatg tttataccag ctttatcatg aaatttgcag gaaatgaaca 155640 gatctagaaa aaagtcatcc atagtgagac ccagagagaa aaacacggta cacattcagt 155700 tataagagta tattctctgt aaagtaaaga atcagactca gagaggctaa gcaacaagga 155760 aggctcagtg tgtggggggc acatgaattt cccttggaag ataaagtaga atagatattg 155820 tgggtagact aggttgggta gggaggagga caagaagaat catgtgggga agggggagga 155880 catggagcaa gcgagagaga gagggagaga gagagagaga gagagagaga gagagagaga 155940 gagagagaga gagagagaga gagagaactg gaaagaggag aaggacattt tggcagtgat 156000 gcagaaacct aacacaatgg aagctcccag caatctacaa gggtgaccta gctaggatcc 156060 ctagaaagtg aggacacaga accttaacta gccatctcct ataactagat atccagtgga 156120 gggattagga taccaactca acctcagcac attcaactta taatttttcc tgcctacaag 156180 atgtactgtg gtgatacaaa aattggggga gtggccaacc aatggctggt tcagcttgaa 156240 acccatagag agagagccca gggctgatac tgactggaag gtcaggaccc agagagaggc 156300 tggatatccc agacacctca gatagaacca aacactattg aaaaaaataa gtcaatgaaa 156360 tgattcctag ttaggttctg ctgtacttgt agacaggagt ctagcaccat catcatgaga 156420 gtggtttcat ctagtaactg atgcaaacag atgcagagac ccacagccta acattaagtg 156480 gagctagagg aattcttgga aggagggcgg agttgtagga gctagctggg tcaaggatgc 156540 cacagaaaag cccacagaat caactaacct ggattaatag gggctcacag acactgaatc 156600 aatagccagt gagcctacat ggactgaccg atgccctctg catatatatt atggttttgt 156660 agcttagtct tctgtgggac ttgtaacagt ggaagcaagg ggtgtctctg tctcttttgg 156720 cctgcttttg ggaccctcct cttttccact gaggcacctt gtccagcctt catacaaggg 156780 aaggggccta gctttgttgc aatttgatat gtcatgtttg gttgctatcc ctgtgaagac 156840 tgcccttttc cgatgggaaa tggaggagga atgggtgaac tgggaggagg caaaggggag 156900 gttcaggagg agtgagggga gaggagacag ggtaagctgt gaactggata taatatatga 156960 ggagaaaaaa taaattaata aaagagagag caacagcaat ccacgttttc tttgcctaag 157020 cagattctac acaggtagta gacgtaaaca attccttttc tgaaacttta tgcatgtgtt 157080 taagtacatg aaattcagtt ttccagcaat gatatcatgc gctatatata gctacataac 157140 ttgtttggtt taaatgacct catttacttc cttgttatta acctaaaagc acctttccac 157200 tatacaaaat tttctctaaa gtacgttttg aggaaacatc tgcttttaca caatggcaga 157260 ttccaatcag cttccctgca aaggtgtggt gctgttgaat actccagcag tagtaacctt 157320 gccttcccac agttttgttt tctgggaggg cacatctagg caacgccttg attttgcttg 157380 tcaatttacc tgaggctttt gggagggcca ggtgatggtt atgtatacac agaaagaggg 157440 tcagatccaa gcacacggct agagcgcggc aggagtggtg aggtccagat cccatgggcc 157500 tagagcatct gacaaagaca gaaaactgga gccaggctca catggaaatc gggaaaacca 157560 tgctgagaag acaacagcaa ggacttactg cattgttcct ttcttttaaa aaaattagat 157620 attttcttta cttacatttc aaattttatc ccctttcttc ctttcccctc tgaaagctat 157680 cctgtctcac cccctccccc ctgcttacta acacatccac tcctacttcc ctgtcctggc 157740 attcccatac actgggacat cgagtcttca caaggctaag ggcctctcct ctcattgatg 157800 tcccacaagg ccatcctcta ctacattgag tccctccgtg tgtactcttt ggttggtggt 157860 ttagtccctg ggagttctgg gggtactagt tggttcttat tgttgttcct cctatggggc 157920 tgcaaaccta gtcagctcct tgggtccttt ctctagctcc tctattgggg accctgtgct 157980 cagtccaatg catggctgtg aacctccact tctgtatttg tcaggcactg ggagagcctc 158040 tcaggagaca gctgtatcag gctcctctca gcaagtactt gttggcatcc acaatagtgt 158100 ctgggtttgg taattgtata tagtacggat cctcaggtag gacagacact ggaggccatt 158160 tccttcagtc tctgcttccc actttctctc tgtatctctt cccatgggta ttttgatccc 158220 ccttctaaga aggatcgaag tatccacacc gtggtcttcc ttcatcttga gattcatgtg 158280 atctgtgaat tgtatcttgg gtattccgag cttttgggct aatatccacc tatgagttca 158340 cagcagcctt atttataata gccagaagca ggaaataacc cagatgtctt tcaacataga 158400 aatgtattat tcctttctta cagtaagagg gagatttcta tttccttaca gggcagtgac 158460 ataatagtag catccttctg attggctaaa ttgttcttca atcacagttg agaagttata 158520 tctgtgagag agggttgact gctaggagaa caatgattag taagttggaa ggacaaacga 158580 ataccttttc tgtcctcatt gtacggatca atacaaatct acttctaaag ccggacgtgg 158640 tggcgcacac ctttgatccc agcactgggg aggcagaggg aggcagattt ctgagttcga 158700 ggccagcctg gtatacaaag tgagttccag gacagccagg gctacacaga gaaaccctgt 158760 ctcaaaaaac aaaaaacagt tccaggactc agcagaactt aggaaattag tctgaacagg 158820 tgagagggtg cgccagagaa ccggacagct tctgggatag gcggaagcac agagccactg 158880 aggcagcacc cttggcgggc tgcagacagc cggccaccgt ccggaccaga ggacaggtgt 158940 ccgcctggct tgggaggcgg cctcagcctc agcagcagcg gtcgccatcc tggttccagg 159000 actccgtgga acttaggaaa ttagtccgaa caggtgagag ggtgcgccag agaaccagac 159060 agcttctggg ataggcggaa gcacagagcc gctgaggcag cacccttggc gggccacaga 159120 cagccggcca ccgtccggac cagaggacag gtgtccgctt ggcttgggag gcggcctcag 159180 cctcaggagc agcggtcgcc atcttggttc cgggactccc tggaacttag gaatttagtc 159240 tgcacaggtg agagtctgca ccacagaagc tgacagcttc tgggaactgc caaagcaaca 159300 cagcttcgga gaaaggccct gttttgggcc ttctttttcg gccaggagga ggtccaaaaa 159360 caagatatct gcgcaccttc cctgtaagag agcttgccag cagagagtgc tctgagcact 159420 gaaactcaga ggagagaatc tgtctcccag gtctgctgat agacggtaac agaatcacca 159480 gaagaacaat ctctaaacag agtcaactct aactactaac tccagagatt accagatggc 159540 aaaaggtaaa cgtaggaatc tttctaacag gaaccaagac cactcaccat catcagaacc 159600 cagcactccc acttcgtcca gtccaggaca ccccaacaca cccgaaaacc tagacctaga 159660 tttaaaagca tatctcatga tgatggtaga ggacatcaag aaggacttta ataaatcact 159720 taaagaaata caggagaaca ctgctaaaaa gttacaagtc cttaaagaaa aacaggaaaa 159780 cacaatcaaa caggtagaag tccttacaga aaaagaggaa aaaacatcca aacaggtgat 159840 ggaaatgaac aaaaccatac tagacctaaa aagggaagta gacacaataa agaaaactca 159900 aagtgaggca acactggaga tagaaaccct aggaaagaaa tctggaacca tagatttgag 159960 catcagcaac agaatacaag agatggaaga gagaatctca ggtgcagaag attccataga 160020 gaacatcggc acaacaatca aagaaaatgg aaaatgcaaa aagatcctaa ctcaaaatat 160080 ccaggaaatc gaggacacaa tgagaagacc aaacctacgg ggataatagg aatggatgag 160140 aatgaagatt ttcaactcaa aggaccaaca aacatcttca acaaaattat tgaagaaaac 160200 ttcccaaatc taaagaaaga gatgcctatg aacatacaag aagcctacag aactccaaat 160260 agactggacc agaaaagaaa ttcctcccga cacataataa tcagaacaac aaatgcacta 160320 aataaagata gaatactaaa agcagtaagg gaaaaaggtc aagtaacata taaaggcaag 160380 cctatcagaa ttacaccaga tttttcacca gagactatga aagccagaag agcctggaca 160440 gatgttatac agacactaag agaacacaaa ttccagccca ggctactata cccagccaaa 160500 ctctcaatta ccatagatgg agaaactaaa gtattccacg acaaaaccaa attcacacat 160560 tatctctcca tgaatccagc ccttcaaagg ataataacag aaaaaaacca atacaagaat 160620 gggaacaacg ccctagaaaa aacaggaagg taatccctca acaaacctaa aagaagacag 160680 ccacaagaac agaatgccaa ctttaacaac aaaaataaca ggaagcaata attacttttc 160740 cttaatatct cttaacatca atggtctcaa ctccctaata aaaagacata gactaacaaa 160800 ctggctacac aaacaagacc caacattttg ctgcttacag gaaacacatc tcagagaaaa 160860 agatagacac tacctcagaa tgaaaggctg gaaaacaatt ttccaagcaa atggtatgaa 160920 gaaacaagct ggagtagcca tcctaatatc tgataagatt gacttccaac ccaaagtcat 160980 caaaaaagac aaggaaaggc acttcgttct catcaaaggt aaaatcctcc aagaggaact 161040 ctcaatactg aatatctatg ctccaaatac aagggcagcc acattcatta aagaaacttt 161100 agtaaagctc aaagcacaca ttgcacctca cacaataata gtgggagact tcaacacacc 161160 actttcacca atggacagat catggaaaca gaaactaaac agggacacac tgaaactaac 161220 agaagtgatg aaacaaatgg atctgacaga tatctacaga acattttatc ctaaaacaaa 161280 aggatatacc ttcttctcag cacctcatgg taccttctcc aaaattgacc acataatagg 161340 tcacaaaaca ggcctcaaca gattcaaaaa tattgaaatt gtcccatgta tcctatcaga 161400 tcaccatgca ctaaggctga ttttcaataa caaaataaat aatagaaaac caacattcac 161460 atggaaactg aacaacactc ttctcaatga taccttggtc aaggaaggaa taaagaaaga 161520 aattaaagac tttttagagt ttaatgaaaa tgaagccaca acgtacccaa acctttggga 161580 cacaatgaaa gcatttctaa gagggaaact catagctctg agtgcctcca agaagaaacg 161640 ggagagagca catactatca gcttgacaac acatctaaaa gctctagaaa aaaaaggaag 161700 caaattcacc caagaggagt agacggcagg aaataatcaa actcaggggt gaaatcaacc 161760 aagtggaaac aagaagaact attcaaagaa ttaaccaaag gaggagttgg ttctttgaga 161820 aaatcaacaa gatagataaa cccttagcta gactcactag agggcacagg gacaaaatcc 161880 taattaacaa aatcagaaat gaaaagggag acataacaac agatcatgaa gaaatccaaa 161940 acaccatcag atccttctac aaaaggctat actcaacaaa actggaaaac ctggacgaaa 162000 tggacaaatt tctggacaga taccaggtac caaagttgaa tcaggatcaa gttgaccttc 162060 taaacagtcc catatcccct aaagaaatag aagcagttat aaatagtctc ccagccaaaa 162120 aaagcccagg accagacggg tttagtgcag agttctatca gaccttcaaa gaagatctaa 162180 ttccagttct gcacaaactt tttcacaaga tagaagtaga atgtactcta cccaactcat 162240 tttatgaagc cactattact ctgataccta aaccacagaa agatccaaca aagatagaga 162300 acttcagacc aatttctctt atgaatatcg atgcaaaaat cctcaataaa attctcgcta 162360 accgaatcca agaacacatt aaagcaatca tccatcctga ccaagtaggt tttattccag 162420 ggatgcaggg atggtttaat atacgaaaat ctatcaatgt aatccattat ataaataaac 162480 tcaaagacaa aaaccacatg atcatctcgt tagatgcaga aaaagcattt gacaagatcc 162540 aacacccatt catgataaaa gttctggaaa gatcaggaat tcaaggccca tacctaaaca 162600 tgataaaagc aatctacagc aaaccagtag ccaacatcaa agtaaatgga gagaagctgg 162660 aagcaatccc actaaaatca gggactagac aaggctgccc actttctccc taccttttca 162720 acatagtact tgaagtatta gccagagcaa ttcgacaaca aaaggagatc aagggataca 162780 aattagaaaa gaggaagtca aaatatcact ttttgcagat gatatgatag tatatataag 162840 tgaccccaaa aattccacca gagaactcct aaacctgata aacagcttcg gtgaagtagc 162900 tggatataaa ataaactcaa agaagtcaat ggcctttctc tatacaaaaa ataatcaggc 162960 tgagaaagaa attagggaaa caacaccctt ctcaatagtc acaaataata taaaatatct 163020 cggcgtgact ctaactaagg aagtgaaaga actgtatgat aaaaacttca agtctctgaa 163080 gaaagaaatt aaagaagatc tcagaagatg gaaggatctc acatgttcat ggattggcag 163140 gatcaacatt gtaaaaatgg ctatcttgcc aaaagcaatt tacagattca atgcaatccc 163200 catcaaaatt ccaactcaat tcttcaatga attagaagta gcaatttgca aattcatctg 163260 gaataacaaa aaacccagga tagcaaaaac tcttctcaag gataaaagaa actctggtgg 163320 aatcaccatg cctgacctaa agctttacta cagagcaatt gtgataaaaa ctgcatggta 163380 ctggtataga gacagacaag tagaccaatg gaatagaatt gaagactcag aaatgaaccc 163440 acacacctat ggtcacttga tcttcgacaa gggagctaaa accatccagt ggaagaaaga 163500 cagcatcatc aacaattggt gctggcacaa ctggttgtta tcatgtagaa gaatgcgaat 163560 tgatccatac ttatctccct gtactaaggt caaatctaag tggatcaagg aacttcactt 163620 aaaaccagag acactgaaac ttatagagga gaaagtgggg aaaagccttg aagatatggg 163680 cacaggggaa aaattcctga acagaacagc aatggcttgt gctgtaagat cgagaattga 163740 caaatgggac ctaatgaaac tccaaagttt ctgcaaggca aaagacaccg tcaataagac 163800 aaaaagacca ccaacagatt gggaaaggat ctttacctat cctaaatcag ataggggact 163860 aatatccaac atatataaag aactcaagaa ggtggacttc agaaaatcaa ataaccccat 163920 taaaaaatgg ggctcagaac tgaacaaaga attctcacct gaggaatacc gaatggcaga 163980 gaagcacctg aaaaaatgtt caacatcctt aatcatcagg gaaatgcaaa tcaaaacaac 164040 cctgagattc cacctcacac cagtcagaat ggctaagatc aaaaattcag gtgacagcag 164100 atgctggcgt ggatgtggag aaagaggaac actcctccat tgttggtggg attgcaggct 164160 tgtacaacca ctctggaaat cagtctggcg gttcctcaga aaactggaca tagtactacc 164220 ggaggatcca gcaatacctc tcctgggcat atatccagaa gatgccccaa ctggtaagaa 164280 ggacacatgc tccactatgt tcatagcagc cctatttata atagccagaa gctggaaaga 164340 acccagatgc ccctcaacag aggaatggat acagaaaatg tggtacatct acacaatgga 164400 gtgttactca gctattaaaa agaatgaatt tatgaaattc ctagccaaat ggatggacct 164460 ggagggcatc atcctgagtg aggtaacaca ttcacaaagg aactcacaca atatgtactc 164520 actgataagt ggatattagc ccaaaaccta gtatacccaa gatacaagat acaatttcct 164580 aaacacatga aactcaagaa gaatgaagac tgaagtgtgg acactatgcc cctccttaga 164640 agtgggaaca aaacaccctt ggaaggagtt acaaagacaa agtttggagc tgagatgaaa 164700 ggatggacca tgtagagact gccatatcca gggatccacc ccataatcag catccaaacg 164760 ctgacaccat tgcatacact agcaagattt tatcgaaagg acccagaggt agctgtctct 164820 tgtgagacta tgccggggcc tagcaaacac ataagtggat gctcacagtc agctattgga 164880 tggatcacag ggcccccaat ggaggagctg gagaaattac ccaaggagct aaagggaact 164940 gcaaccctat aggtggaaca acattatgaa ctaaccagta ccccggagct cttgactcta 165000 gctgcatatg tatcaaaaga tggcctagat aggccatcac tggaaagaga ggcccattgg 165060 acacgcaaat tttatatgcc ccagtacagg ggaacgccag ggccaaaaag ggagagtggg 165120 tgggtagggg agtgggggtg ggtgggtatg ggggactttt ggtatagcat tggaaatgta 165180 aatgagctaa atacctaata aaaaataaaa acaaaaaaca aaaaacaaac aacaacaaca 165240 acaaaaaacc caaaacaaac aaatctactt ctaacaatct cactagacta tgggggctgg 165300 aaaccagggc ccccttcact gttattacta ctttcttctt ttccaacatt acaagaccat 165360 gatactattt ttgggaaatg tcatatggaa aattgacacc tgttctgctc atatgttccc 165420 acacaggaca gtttcaacag aatttgcatg gcttttccca tgtcttattt cttttgttcc 165480 tacttgttga tataaaagca aagcaaagca aagcaaagca aagcaaagca aagcaaagca 165540 aagcaaagca aagcaaagca aagcaaagca aaacaaaaca aaacaaaaca agcctcacga 165600 aacagtatag tgtcactgta ttagagaaga tcagaatccc agccccagcc acacagaagc 165660 aatgtgagtg agcctcaggc ccttgctcct gctaagttcc cattggtgaa ttcctaagtg 165720 gaaccatact gtggctactg tgaaaaacac ggaagcggcc acacaaaaac caccctgaag 165780 tatcaaattc tgtttcttta gctgtattcc taggattact ggatcatgtg gggattttac 165840 tttaagtcag agtgtacata ctgctgtgtt ctgctctgta ggagagaaga gaagagagag 165900 agagacatag atttggtacc ttgtgatctc aactttatta tttttttctt aaaagtgata 165960 gcatcaaaag aacctatctt tttaaacttc tgtgggtctc agaacatata atgtgtgaat 166020 ttacttagaa atgtggataa actattgcaa ttatcaggta ataattttgc ctaatagaaa 166080 tagagttaca tacatcttag accagatttc tgagttcact cagatctcag cttgtacttg 166140 tagaacagga tatcaaaaaa gctcttagaa gtagaaaaag tgtgtgtgtg tgtgtttatg 166200 tatgtatgta tttgtgtgtg tgcttgtctg tgtgtttgtg tgcttgtgta tatgtgcatg 166260 tatgtgttta tgagtaggtg tgcttatgta tatgtatgca tgcatgtata catttgtgtt 166320 tttgtaaagt ttgtatattt ctaccataca tatacacgct agaaaatatc tggactgtgt 166380 tgctaagttt tttgaggtaa taattcctgg gaagagatta cttgactttc tgaagctcta 166440 acatagacta cgtataattt gaaaggccat gagagttagt ataacttgga tgcaaagacg 166500 actgtgaata taacactctt tccagctcta tgacataata tattccatct atttccttct 166560 gggtgcatag tcctacactg gggtccttga ttgcctgtgt tcattaatga gtttgtgtgt 166620 ctacatctgg ataaaaagct acggaaagac agactattgt acatgtcaca cgaggaaact 166680 ggggcactcc tggatgttgc agggatggca aagaggggag ggataagagg tgcagaaaaa 166740 aaaaatgaga atataaatcc ctatcttcag ttaagtggat tcaatctaat ctaaaagtct 166800 ttcactttgc taaatatttg gtataggcta gtagtggagg gtgtctgggc catctggaga 166860 cttcaggaca aacaggatgg tgaagagcta ggtccctggg aagctgcaga aagagttcgg 166920 ctttccacag tctgtgggta cttaactgaa ttacacatgc actttcatga atatgatggg 166980 gtctaaattt actatattac atacgtggcc atatatttat ttctattgta atttaactta 167040 ccagtaggag aagcaacaca tttgttgtct tgtttactat aatgtaattg ttcataagaa 167100 agataatcta aattggatgt acttaaattg ctgtgtggga acagttctgc cttgggggga 167160 catttgttag tctctaccag cacatcagtt caacaggtta gtgatagtgg tcagaattct 167220 gctatgcaca agagagaccc ctaagaattc ctgaccccaa accccaaaaa tactagctgg 167280 ttttgtatgt caacttgaca cagctggagt tatcacagag aaagaagcgt cccttgagga 167340 aatgcctcca tgagatctag ccgtaaggca tttctcaatg tgggtggtgc catgcctgga 167400 ctggtagtcc tgggttctat aagaaagcaa gctgagcaag ccacacaaag caatccagta 167460 aggagcactc ctccatggcc tctgcatcag ctcctgcctc taagttcctg tcctgtgtga 167520 gttcctgttc cagcttcctt tggtgatgaa cagcaatgtg gacgtgttag ctcaataaac 167580 cctttcctcc ctaacttgct tcttgatcat gttttgtgca ggaacacaaa gcctgactaa 167640 gacacccaat taggcccagc cgcaatcttg tgttagaaca atcacttact ttacagagag 167700 aaactgagca ccaaaggggc cagtgatatg tgcaaagtcg ctctgagcat ataagagagg 167760 taggtcctct agtgtattta catcgtgcca tttagcttca aagagctagt attccacatg 167820 gaactgctga aaaaccaata ttgctgggaa ccccttgcac ttcagatatg gtacataact 167880 gcacagtaaa catcagtcca cagctagcca tagttaggcc aggcaagaag aaacagagaa 167940 tttaattatg taacacctat tcagatattg tatgaaaacc attttcatat ctgaccaagt 168000 tactgtccca tgtactggat cttcacacac ctcactactg cctggaggtt gtaagaactt 168060 gcatttctag aacctacaaa gggaagttct aagtgtgtct gccctgaggc ccaaagacgg 168120 gcatttccaa atgttccatt cagatgctga catagctagt agctagcttt ctcagaccac 168180 tgagaaacac tgcctaacat ttgatgggga aatggcaaat gctggtctaa gagtaaactt 168240 gaatctcacc cttcatgtaa tctcacttta agagtgatta atgttaattc acacaaagga 168300 ctataatcat ataagtggta atttagacat aattcaaatt tcaaaaagtc taaaaaggaa 168360 gaaatctgta ggtttttgat agcctataga gacaacatta aggaataatc atatgttatt 168420 tgaggagaag agtgataccc taaatataat aagtattata taaaaatatt atatataaaa 168480 taccctaaat tggaagacat ccaaacaaat aatataaata ttattctgta tgcattcttt 168540 atttttaaca ttttatttct gctagactga gtgaccttga tctattgggc ctgccgagct 168600 gtatctacgg ggatcgttgc tattgacatc agtaatataa aatcaggcct ttagggagcc 168660 gtaactgtct cttcaaatga tttgggaaaa tgtgtacatc ttcaatcaat taaatacagg 168720 acaaatttag tcaatcacaa atgatcaaca cgcccctgtt cattgtgctt agcagtatga 168780 aaatggcacc caggcaaatt gatttcggta acactccttt tcattctttt aattcaatag 168840 tgagaagaat ataaggcagt tttcaatgtt ctatccacag taatcctgta gttagtctgc 168900 cttactgctt acaccagagc tcatttgaag acacccaagc aaatgacagg aaacttttaa 168960 ctctggtcaa gtcccaatca cagacccttg cttgccaagg acacaaagga agccaaactt 169020 tcaaacatgc tgcattgatc tccaactttt taaatccctc tgtcatttta aatgaggtgc 169080 actcggttgt gtcatcatct cggttttaat tgtgtgaaaa tttcctgcca atctcacacc 169140 gctgcggcaa cctcaccttg ctacttgccc tgcaagttct gcagtgtgcc gttctgagta 169200 tgccgtttta actagttctt gcagcaggac acaaagcgag atagtctgat agaaccagtt 169260 ctcctctggt tttaccttta ctcttagatg agttaagggt cacatcaaac cagggctcag 169320 cccgccagat ctcctaagca cagcccctcc tgacccaatg cagttaaccc aacctcattc 169380 agcgctagta tcaaatgaca ctggagctgc tgcagtatgc atcccgagac taagtaggca 169440 ggatttatta tcagcagaag tcccctaact accaggttat tcaagctccg ttcttgtcac 169500 aaacaggcgc ggcggaagac acagtgcagc agactcagag ctcatttaca agacaagcga 169560 attctcagtt agagacaagg gcagcgcggc agcgaactgc agtaaatctt ttcacgctca 169620 cagcaacatc taacaatgct ctcctgcaac gcctcagatc aaacgaatcc tacttggttt 169680 aaacatcaaa tcaacaccat aaaaaaggct tcattagcaa agttcaattt aggatgtttt 169740 taatcgtgtc ttaattctag aaccagtgcg agactttcca tgcttattca agcatgctga 169800 cagaattgga acctcttaga attgcctacc tgcacctatc agcctggctg acaggagccc 169860 gccaaaggat taaaaaaaaa caaaacccaa aacataaaat catgcaaaaa aatatttacc 169920 cccgaaagat gtatgtagtt aaagctcagc ttcctgcagc ctcgatagcc cctgaagtgt 169980 taatctgaag aaacagttcc atgagtttcc acaggccggt agtgagtctc ctacacttga 170040 cctagacaga cttacat 170057 <210> 12 <211> 170057 <212> RNA <213> Mus musculus <400> 12 uaaaauaaaa aauuaauuuu auuagauuug cacauuuuuu aauugugauu agcaucauuu 60 ugggcuaaua guagcauuuu ccaacaugca guucaugaau acgguuugcc uaaauauuuu 120 uuuuuuaaga aaaagaggug ccuacggucu gcuucuguaa gaaacacaaa uaucuugaug 180 uaauugacua uauaagugua auccucucug auuuugagga aaagaaauuc ugaagcccac 240 auuuauauuu agaacaaucu aaagaagcau gauuucaaag caaagaaaaa uaaacagaaa 300 uuggggaaau aaagaaaaaa augagaaaaa aaagcacucu ggucaucugu uagcacaaac 360 acuacaauaa auauaaauca aauguuauac cuuuuccaau ugcaaaucau aauuuggaug 420 ugaaguugug aguguauuuu 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gcuugacaac acaucuaaaa gcucuagaaa aaaaaggaag 161700 caaauucacc caagaggagu agacggcagg aaauaaucaa acucaggggu gaaaucaacc 161760 aaguggaaac aagaagaacu auucaaagaa uuaaccaaag gaggaguugg uucuuugaga 161820 aaaucaacaa gauagauaaa cccuuagcua gacucacuag agggcacagg gacaaaaucc 161880 uaauuaacaa aaucagaaau gaaaagggag acauaacaac agaucaugaa gaaauccaaa 161940 acaccaucag auccuucuac aaaaggcuau acucaacaaa acuggaaaac cuggacgaaa 162000 uggacaaauu ucuggacaga uaccagguac caaaguugaa ucaggaucaa guugaccuuc 162060 uaaacagucc cauauccccu aaagaaauag aagcaguuau aaauagucuc ccagccaaaa 162120 aaagcccagg accagacggg uuuagugcag aguucuauca gaccuucaaa gaagaucuaa 162180 uuccaguucu gcacaaacuu uuucacaaga uagaaguaga auguacucua cccaacucau 162240 uuuaugaagc cacuauuacu cugauaccua aaccacagaa agauccaaca aagauagaga 162300 acuucagacc aauuucucuu augaauaucg augcaaaaau ccucaauaaa auucucgcua 162360 accgaaucca agaacacauu aaagcaauca uccauccuga ccaaguaggu uuuauuccag 162420 ggaugcaggg augguuuaau auacgaaaau cuaucaaugu aauccauuau auaaauaaac 162480 ucaaagacaa aaaccacaug aucaucucgu uagaugcaga aaaagcauuu gacaagaucc 162540 aacacccauu caugauaaaa guucuggaaa gaucaggaau ucaaggccca uaccuaaaca 162600 ugauaaaagc aaucuacagc aaaccaguag ccaacaucaa aguaaaugga gagaagcugg 162660 aagcaauccc acuaaaauca gggacuagac aaggcugccc acuuucuccc uaccuuuuca 162720 acauaguacu ugaaguauua gccagagcaa uucgacaaca aaaggagauc aagggauaca 162780 aauuagaaaa gaggaaguca aaauaucacu uuuugcagau gauaugauag uauauauaag 162840 ugaccccaaa aauuccacca gagaacuccu aaaccugaua aacagcuucg gugaaguagc 162900 uggauauaaa auaaacucaa agaagucaau ggccuuucuc uauacaaaaa auaaucaggc 162960 ugagaaagaa auuagggaaa caacacccuu cucaauaguc acaaauaaua uaaaauaucu 163020 cggcgugacu cuaacuaagg aagugaaaga acuguaugau aaaaacuuca agucucugaa 163080 gaaagaaauu aaagaagauc ucagaagaug gaaggaucuc acauguucau ggauuggcag 163140 gaucaacauu guaaaaaugg cuaucuugcc aaaagcaauu uacagauuca augcaauccc 163200 caucaaaauu ccaacucaau ucuucaauga auuagaagua gcaauuugca aauucaucug 163260 gaauaacaaa aaacccagga uagcaaaaac ucuucucaag gauaaaagaa acucuggugg 163320 aaucaccaug ccugaccuaa agcuuuacua cagagcaauu gugauaaaaa cugcauggua 163380 cugguauaga gacagacaag uagaccaaug gaauagaauu gaagacucag aaaugaaccc 163440 acacaccuau ggucacuuga ucuucgacaa gggagcuaaa accauccagu ggaagaaaga 163500 cagcaucauc aacaauuggu gcuggcacaa cugguuguua ucauguagaa gaaugcgaau 163560 ugauccauac uuaucucccu guacuaaggu caaaucuaag uggaucaagg aacuucacuu 163620 aaaaccagag acacugaaac uuauagagga gaaagugggg aaaagccuug aagauauggg 163680 cacaggggaa aaauuccuga acagaacagc aauggcuugu gcuguaagau cgagaauuga 163740 caaaugggac cuaaugaaac uccaaaguuu cugcaaggca aaagacaccg ucaauaagac 163800 aaaaagacca ccaacagauu gggaaaggau cuuuaccuau ccuaaaucag auaggggacu 163860 aauauccaac auauauaaag aacucaagaa gguggacuuc agaaaaucaa auaaccccau 163920 uaaaaaaugg ggcucagaac ugaacaaaga auucucaccu gaggaauacc gaauggcaga 163980 gaagcaccug aaaaaauguu caacauccuu aaucaucagg gaaaugcaaa ucaaaacaac 164040 ccugagauuc caccucacac cagucagaau ggcuaagauc aaaaauucag gugacagcag 164100 augcuggcgu ggauguggag aaagaggaac acuccuccau uguugguggg auugcaggcu 164160 uguacaacca cucuggaaau cagucuggcg guuccucaga aaacuggaca uaguacuacc 164220 ggaggaucca gcaauaccuc uccugggcau auauccagaa gaugccccaa cugguaagaa 164280 ggacacaugc uccacuaugu ucauagcagc ccuauuuaua auagccagaa gcuggaaaga 164340 acccagaugc cccucaacag aggaauggau acagaaaaug ugguacaucu acacaaugga 164400 guguuacuca gcuauuaaaa agaaugaauu uaugaaauuc cuagccaaau ggauggaccu 164460 ggagggcauc auccugagug agguaacaca uucacaaagg aacucacaca auauguacuc 164520 acugauaagu ggauauuagc ccaaaaccua guauacccaa gauacaagau acaauuuccu 164580 aaacacauga aacucaagaa gaaugaagac ugaagugugg acacuaugcc ccuccuuaga 164640 agugggaaca aaacacccuu ggaaggaguu acaaagacaa aguuuggagc ugagaugaaa 164700 ggauggacca uguagagacu gccauaucca gggauccacc ccauaaucag cauccaaacg 164760 cugacaccau ugcauacacu agcaagauuu uaucgaaagg acccagaggu agcugucucu 164820 ugugagacua ugccggggcc uagcaaacac auaaguggau gcucacaguc agcuauugga 164880 uggaucacag ggcccccaau ggaggagcug gagaaauuac ccaaggagcu aaagggaacu 164940 gcaacccuau agguggaaca acauuaugaa cuaaccagua ccccggagcu cuugacucua 165000 gcugcauaug uaucaaaaga uggccuagau aggccaucac uggaaagaga ggcccauugg 165060 acacgcaaau uuuauaugcc ccaguacagg ggaacgccag ggccaaaaag ggagaguggg 165120 uggguagggg agugggggug gguggguaug ggggacuuuu gguauagcau uggaaaugua 165180 aaugagcuaa auaccuaaua aaaaauaaaa acaaaaaaca aaaaacaaac aacaacaaca 165240 acaaaaaacc caaaacaaac aaaucuacuu cuaacaaucu cacuagacua ugggggcugg 165300 aaaccagggc ccccuucacu guuauuacua cuuucuucuu uuccaacauu acaagaccau 165360 gauacuauuu uugggaaaug ucauauggaa aauugacacc uguucugcuc auauguuccc 165420 acacaggaca guuucaacag aauuugcaug gcuuuuccca ugucuuauuu cuuuuguucc 165480 uacuuguuga uauaaaagca aagcaaagca aagcaaagca aagcaaagca aagcaaagca 165540 aagcaaagca aagcaaagca aagcaaagca aaacaaaaca aaacaaaaca agccucacga 165600 aacaguauag ugucacugua uuagagaaga ucagaauccc agccccagcc acacagaagc 165660 aaugugagug agccucaggc ccuugcuccu gcuaaguucc cauuggugaa uuccuaagug 165720 gaaccauacu guggcuacug ugaaaaacac ggaagcggcc acacaaaaac cacccugaag 165780 uaucaaauuc uguuucuuua gcuguauucc uaggauuacu ggaucaugug gggauuuuac 165840 uuuaagucag aguguacaua cugcuguguu cugcucugua ggagagaaga gaagagagag 165900 agagacauag auuugguacc uugugaucuc aacuuuauua uuuuuuucuu aaaagugaua 165960 gcaucaaaag aaccuaucuu uuuaaacuuc ugugggucuc agaacauaua augugugaau 166020 uuacuuagaa auguggauaa acuauugcaa uuaucaggua auaauuuugc cuaauagaaa 166080 uagaguuaca uacaucuuag accagauuuc ugaguucacu cagaucucag cuuguacuug 166140 uagaacagga uaucaaaaaa gcucuuagaa guagaaaaag ugugugugug uguguuuaug 166200 uauguaugua uuugugugug ugcuugucug uguguuugug ugcuugugua uaugugcaug 166260 uauguguuua ugaguaggug ugcuuaugua uauguaugca ugcauguaua cauuuguguu 166320 uuuguaaagu uuguauauuu cuaccauaca uauacacgcu agaaaauauc uggacugugu 166380 ugcuaaguuu uuugagguaa uaauuccugg gaagagauua cuugacuuuc ugaagcucua 166440 acauagacua cguauaauuu gaaaggccau gagaguuagu auaacuugga ugcaaagacg 166500 acugugaaua uaacacucuu uccagcucua ugacauaaua uauuccaucu auuuccuucu 166560 gggugcauag uccuacacug ggguccuuga uugccugugu ucauuaauga guuugugugu 166620 cuacaucugg auaaaaagcu acggaaagac agacuauugu acaugucaca cgaggaaacu 166680 ggggcacucc uggauguugc agggauggca aagaggggag ggauaagagg ugcagaaaaa 166740 aaaaaugaga auauaaaucc cuaucuucag uuaaguggau ucaaucuaau cuaaaagucu 166800 uucacuuugc uaaauauuug guauaggcua guaguggagg gugucugggc caucuggaga 166860 cuucaggaca aacaggaugg ugaagagcua ggucccuggg aagcugcaga aagaguucgg 166920 cuuuccacag ucugugggua cuuaacugaa uuacacaugc acuuucauga auaugauggg 166980 gucuaaauuu acuauauuac auacguggcc auauauuuau uucuauugua auuuaacuua 167040 ccaguaggag aagcaacaca uuuguugucu uguuuacuau aauguaauug uucauaagaa 167100 agauaaucua aauuggaugu acuuaaauug cuguguggga acaguucugc cuugggggga 167160 cauuuguuag ucucuaccag cacaucaguu caacagguua gugauagugg ucagaauucu 167220 gcuaugcaca agagagaccc cuaagaauuc cugaccccaa accccaaaaa uacuagcugg 167280 uuuuguaugu caacuugaca cagcuggagu uaucacagag aaagaagcgu cccuugagga 167340 aaugccucca ugagaucuag ccguaaggca uuucucaaug uggguggugc caugccugga 167400 cugguagucc uggguucuau aagaaagcaa gcugagcaag ccacacaaag caauccagua 167460 aggagcacuc cuccauggcc ucugcaucag cuccugccuc uaaguuccug uccuguguga 167520 guuccuguuc cagcuuccuu uggugaugaa cagcaaugug gacguguuag cucaauaaac 167580 ccuuuccucc cuaacuugcu ucuugaucau guuuugugca ggaacacaaa gccugacuaa 167640 gacacccaau uaggcccagc cgcaaucuug uguuagaaca aucacuuacu uuacagagag 167700 aaacugagca ccaaaggggc cagugauaug ugcaaagucg cucugagcau auaagagagg 167760 uagguccucu aguguauuua caucgugcca uuuagcuuca aagagcuagu auuccacaug 167820 gaacugcuga aaaaccaaua uugcugggaa ccccuugcac uucagauaug guacauaacu 167880 gcacaguaaa caucagucca cagcuagcca uaguuaggcc aggcaagaag aaacagagaa 167940 uuuaauuaug uaacaccuau ucagauauug uaugaaaacc auuuucauau cugaccaagu 168000 uacuguccca uguacuggau cuucacacac cucacuacug ccuggagguu guaagaacuu 168060 gcauuucuag aaccuacaaa gggaaguucu aagugugucu gcccugaggc ccaaagacgg 168120 gcauuuccaa auguuccauu cagaugcuga cauagcuagu agcuagcuuu cucagaccac 168180 ugagaaacac ugccuaacau uugaugggga aauggcaaau gcuggucuaa gaguaaacuu 168240 gaaucucacc cuucauguaa ucucacuuua agagugauua auguuaauuc acacaaagga 168300 cuauaaucau auaaguggua auuuagacau aauucaaauu ucaaaaaguc uaaaaaggaa 168360 gaaaucugua gguuuuugau agccuauaga gacaacauua aggaauaauc auauguuauu 168420 ugaggagaag agugauaccc uaaauauaau aaguauuaua uaaaaauauu auauauaaaa 168480 uacccuaaau uggaagacau ccaaacaaau aauauaaaua uuauucugua ugcauucuuu 168540 auuuuuaaca uuuuauuucu gcuagacuga gugaccuuga ucuauugggc cugccgagcu 168600 guaucuacgg ggaucguugc uauugacauc aguaauauaa aaucaggccu uuagggagcc 168660 guaacugucu cuucaaauga uuugggaaaa uguguacauc uucaaucaau uaaauacagg 168720 acaaauuuag ucaaucacaa augaucaaca cgccccuguu cauugugcuu agcaguauga 168780 aaauggcacc caggcaaauu gauuucggua acacuccuuu ucauucuuuu aauucaauag 168840 ugagaagaau auaaggcagu uuucaauguu cuauccacag uaauccugua guuagucugc 168900 cuuacugcuu acaccagagc ucauuugaag acacccaagc aaaugacagg aaacuuuuaa 168960 cucuggucaa gucccaauca cagacccuug cuugccaagg acacaaagga agccaaacuu 169020 ucaaacaugc ugcauugauc uccaacuuuu uaaaucccuc ugucauuuua aaugaggugc 169080 acucgguugu gucaucaucu cgguuuuaau ugugugaaaa uuuccugcca aucucacacc 169140 gcugcggcaa ccucaccuug cuacuugccc ugcaaguucu gcagugugcc guucugagua 169200 ugccguuuua acuaguucuu gcagcaggac acaaagcgag auagucugau agaaccaguu 169260 cuccucuggu uuuaccuuua cucuuagaug aguuaagggu cacaucaaac cagggcucag 169320 cccgccagau cuccuaagca cagccccucc ugacccaaug caguuaaccc aaccucauuc 169380 agcgcuagua ucaaaugaca cuggagcugc ugcaguaugc aucccgagac uaaguaggca 169440 ggauuuauua ucagcagaag uccccuaacu accagguuau ucaagcuccg uucuugucac 169500 aaacaggcgc ggcggaagac acagugcagc agacucagag cucauuuaca agacaagcga 169560 auucucaguu agagacaagg gcagcgcggc agcgaacugc aguaaaucuu uucacgcuca 169620 cagcaacauc uaacaaugcu cuccugcaac gccucagauc aaacgaaucc uacuugguuu 169680 aaacaucaaa ucaacaccau aaaaaaggcu ucauuagcaa aguucaauuu aggauguuuu 169740 uaaucguguc uuaauucuag aaccagugcg agacuuucca ugcuuauuca agcaugcuga 169800 cagaauugga accucuuaga auugccuacc ugcaccuauc agccuggcug acaggagccc 169860 gccaaaggau uaaaaaaaaa caaaacccaa aacauaaaau caugcaaaaa aauauuuacc 169920 cccgaaagau guauguaguu aaagcucagc uuccugcagc cucgauagcc ccugaagugu 169980 uaaucugaag aaacaguucc augaguuucc acaggccggu agugagucuc cuacacuuga 170040 ccuagacaga cuuacau 170057 <210> 13 <211> 123 <212> DNA <213> Mus musculus <400> 13 gtttcattgg tcagtttaac agcaaatgcc ttgggttact ctgaactcgg ggccatcaaa 60 tccctaagga cactaagagc tctgagaccc ctaagagcct tatcacgatt tgaagggatg 120 agg 123 <210> 14 <211> 7597 <212> DNA <213> Mus musculus <400> 14 gtaagaaaaa ggaaaactct gcagcgttgt atattgtcaa agctaggctg agttcaactt 60 aactaacgaa aaacacgtgc atgcaaaagg aatggcaacc ctttgcaaac ttgctacttt 120 acccttttct ctgttgcata tttacttctt ggtgatatgc aagagaaaat cggcctcttt 180 gaaaatgatt taatatcatt tatctgcttt gctaattaaa atgaccttag ttcataatcg 240 atcttgggag tttccttata attcctaata caaaggggga ggggcagata ctctcttaaa 300 gaactaagtt gagtcatgta ataattacct agagataatt ttgtttcata tcgttctcct 360 ctatgacagc ccatcagtac ttaagggatc ctatggaaag taatgtgaat cacaaatgtg 420 tatgaataca aaggaaaaaa tgaagaattg ttaaatgttt tgtctttaca atgccaaaat 480 tctcattatt tgaatatatc caagggcaga tattaaccat tgactggagt ataataatac 540 tgcctcaact gtaactaaat taatgacatt gaataagtaa gacactaatt taattactat 600 aaatacatac acatcttatg acaatacagc tgataaggaa aaagaacatg tatttttatt 660 cattgccata catggctcgt caaccttaac ttaaacctcg gttctcagtt acacagagtt 720 ttatgttgct cttttgagca aagcattatt cccctctcca taattcaaca cgtatcagat 780 ttttgcattt attggctcat tgttatgatg attatttcaa agcattatac aatcatttat 840 agaagatgtg ccgtgtgaaa attatttttt tattaagatc caaaatttac gctctttaaa 900 ccaatcagat gaaatgtata aggcaaagag tgctcattgt cctgacactt acaaaccaag 960 gctccaacaa acaggctcct ctctgcacca catagagggc tttcagcctg tgtcccccca 1020 taaaaaccta ttataaattt tattatacta tactgtaaga aacctgtcca atttttaatt 1080 tctctagcac atatgaaaac ttctcttcag tagatccaag taagcacaaa ggagctttga 1140 ttctcacaca agaaatcaca tttgtattaa aaatgtatca taaattttct cccaattatg 1200 caaaacttaa atgcttttcc aattaaaaga gcactttcgt ttcagaatag caatttcagt 1260 tgtcaaggaa aacattgttt ttatacattt tatataaaaa tacatgagct aaatttaaat 1320 tcacattttt caacttttta tggttttttt atgtttcttt ttctttcgca ttttttaaca 1380 atccagccat tacctctcct ccctgtcccc ctcctatagt ttctcatctc attcctcctc 1440 ccccttgcct ctgagaggat gctccctccc tcactaggcc tccctcttcc ccagggcttc 1500 aagttcctca aggattatac acatcttctc ccactgagac caggccaggc agtcctctgc 1560 ttctgcccag cctgtgtatg ttcctgcttg gtagctcagt ctctggaagc tccctggggt 1620 ctgggttagt tgggactgct ggtcttccta tggagttacc ctccccttca acttcttcaa 1680 tccttcccct aattcaacca caggtatcca gacttcagtc caatggttga gtgtaaatat 1740 tggcatctgt ctctgtcagc tgttgttagg ggctcagagg acagccatgc taggctcctg 1800 cctacaagca gcacaccata acatcagtaa tagtgtcagg cctttaatga ataatgctac 1860 gtatataagg ttgttagatt atacttcaac tttgatcttt tagaatatta ttaaatccag 1920 tcgtttattt tttatatgta atattgactt tccataacaa atgagtctat tttccttttg 1980 tgtagaaata actttatcaa ttattgttaa taatgctttt gtcaattatt gttgatatgc 2040 ttctcttttt taaaactgga gtcatcaaaa caaaaattct gggtagatat tacgaagctg 2100 actccttggt cagcttggca catagtgaga ccacaaatat ctcaaggtca cggcaattcc 2160 tcaccaccag tttggcattg tgaagtcaaa accaaccttc tgttgattct ggtttttgta 2220 tttctagtat gagacatttt ctactttgta agagtatata actgtggatg gcggcgaggt 2280 tgggcatgat gatgattgta agcgggaagt gagctagagt atcttcagaa actctcactt 2340 tatcctcctt ggcagcatag aaccgcaatc gctgtgtccg agtgtcaacc aggcagtcat 2400 tttgttttgg gttttttgtc actctttcaa agcatgtgct tctacgcaac actaccaaac 2460 acagcatgct gcatagtgct tgagaaggag ttagaaagta acaaacgagt tatcatcacg 2520 ttgccctttg tgttttgcat gtcttatgca cacttttggc tgacagcttt tgaacattta 2580 ttgtatttca aatttccagt ccaaattttt ttttcaactt gtgaaattga acggaatgaa 2640 ccgatgtcgt gaatacctag ggtcaaataa aacttgtatt taaattcgta gttttaattt 2700 cccaagctgg gaaaatcgta aaaacctttt ccaaagaact caagtcttag ttgctaggga 2760 aacaggcagt gagcatcata tacaaaaagt aacaccaaat gttctgtcat atcagctttc 2820 taactaataa taaactatat atttctattt tatataggat aatcttgctc caacttggat 2880 ggggtggagc ggtggttcct cccctcagcc ctttattatg ggtactgtat tacccctttt 2940 gctaccttta atccttgcac tgtgacttat gtgtagtggg attgagggag ggagtgggaa 3000 gggtacaatt gcaccacagt agggacaata caggatttat ttccaaatcc actactttta 3060 atgagcttaa acttcttttg ggaaaaaaaa agttatctct gacttaccat ctgtggatta 3120 taaccccaga agtacatatc tttattacgt ttcactgaat atgatttagc tatttatact 3180 tcattgtcca tttatgggga aattactcaa ttggtgaggg tgggggaccc tggtgtagga 3240 tgctgatgaa aacgttttca tttgtcaagc tcatggtagt gacagagcat atagtcctta 3300 ttttttcaac acactgctct ggtccctcaa tgggccagtc acattccatc agttgatcgt 3360 tgatgtgtgc gagcagtggc taaaggtaca acaggccagg tatctcaggg ttgccaatgg 3420 ttatgatcat tctcatcttt attgcataaa aatgtgttat ttgcagaaag tagcaaggca 3480 agatccctgt gaaacaaggg aatacaaaaa aaaaaaaaga tgtgctttaa gttataaaac 3540 caaaacatgt gaaaagtcaa cttcattgaa gtataaagaa taggatatgc atgaaaaaca 3600 aaaaaatcat gagcactaag aaattggtgt ataagccaac tccttgtaag ctaccccaat 3660 taacttccca gaatcttaga aggcatcaca gtgcacccca aaataaaaag ccaaactgac 3720 acttctgctt cctcttaaaa tgtaggagtc ttggataaga aagataattt ttattgtttg 3780 gaagaaaaaa aaattgtttg gataattgag gcatttatct atcaaaaata tttatcttaa 3840 taaaatttca caacactgat ttagttgttg gcttttctaa aaatttttta tatttcatat 3900 taagaactca tgatttttac tttccatttt ttaaattctt attcacatat ggtttttctc 3960 tatttcttag aaaagctata gaacccatgg tttccggtga cttaaaaaac taatctaaat 4020 gtcttcactt agatgatact ttcaaatgca ctgaaatttc taatatcaac aagaatattt 4080 gcctggtcct aatttttcac tgatttaata aaaagtatga accctaaaga agaaatagac 4140 ttgaagaact ggttgtgtga caatacagaa attctgctgg gagatgtcct tttaaaacat 4200 tgttagaaga gacaacctct acaatccacc cattaagcat acttctctct tagacatctc 4260 cttttatgta ccttataacc tcaatgtgtt ctttccaatt gacttagacc aacacttccc 4320 agcgcatccc acatgggagc caattactga ctctccctag agactgcaaa gaattaatat 4380 tgtagaacca agggatggtt gggctcttgg gagaggcaat ccgtttgtga tcttttgctc 4440 tggatgttaa tgaaatcgca actttaagtg gattttcagt ggcaaatcct ctgatcctat 4500 gccaaatgtt ctctaagaca aacatccttg taaaataaat gtctcactgg gccaaatcta 4560 tggcaaattt gcacgttttc ctgaactgca ttcctatata gtatttgcca tcctgaattc 4620 actaatgggc attactttta attcaaaacc agtcccttct tcaaaggaaa tctctcccat 4680 ttattacatt atgcaaactg ctttcttatg cagtggttaa atccttagcc aggcaagtat 4740 gaggactgga atttggatat ccagaaccct cagaaatgtc ggatgggcat agtagcttac 4800 atgtaattcc agagctagaa agatgaaact agccctgtcc tcaagctctg aattcagttg 4860 gtgcaataaa taagaaagaa tccccccccc cgacccctac atctctttcc tctacatcta 4920 tacatgtatt tcccatacag ctctatgctt ccacatatat gctcacatat gtgcatgcac 4980 acttgcacac atatgtacac ttgacacatt gaagcatcat aatctaacaa ttggaatata 5040 agaaaatatt taactttcac acagagcagt cagagaaaac cataagaggt tgaaactctt 5100 gaaaaaactt gcaggataaa cagaaaagag tatgagatgc caattctggt ctactttctg 5160 aacctaactt gttttacctt cattagtcta attttccaaa tgaaccccaa gcaccaaatt 5220 gtccttattg ctctttccag tactaaatta taattcctca attcgaaggc aaacactctc 5280 atctttgtta aggatgtgta gagttagact caataaacga catgtatatt tgagctaaag 5340 cctggaggag ggagattatt tcaagggcaa gtacttggca gggagtttca aagaaagaag 5400 gctctcaatt ctcagactaa caccttagcg tggagtgact gtcacagagg agggtgaagt 5460 gtatgtcacc agttagggaa gctgaaaggg gaaatgtatc aggcttgtga gaatccttca 5520 gcagccaagt ctagcacctg agcacaatcc ccagaactga ccccacatgg tggaaaggag 5580 aggaataatt cctgcaaatt ttcctgtgac ctccacccaa gtgctataga aaatgcatgc 5640 atgcccacat gcacacacaa ataaacatag ttgcaaactg ttttgaggaa aataacctca 5700 caaactgtcg agtgatgtaa atgccaaaga aagagaaatg ttttctaatg gctagagaac 5760 cattaaggaa tttttcaaaa tgggacatgg gatagataaa tttagtatcc atactgaaag 5820 aaggcaagca aataaaatct gataagaatg taattcttag taaccgagga cagagcgaag 5880 atagagaaca gggccaatgg ccaaggtgga aaggtttgaa ggaagcagca tgaaacctac 5940 agacttgtac caaaatgttc agtgtcatga gtgttaaaag tgaaaagctt gcatgttagt 6000 atggatttca tatcctcggc agacagagca cctcactgtg agtgggagat gaagtattca 6060 gaaatgagaa acaactactc aatttcagtg ttcatatctc aaatccaata aacaacttta 6120 ggggtacaat tttttaaaaa attacattaa aatgttttta aatctcttct taataattta 6180 aaaattaaat tgaaaataac tttaaaaagt aatatataca ggaaagcctg tgtgctaatt 6240 ttttagggag gccataaagg gagatagttg ctcattaatt tctacacatc agcctatctt 6300 tggcttctgc cttgatagcg cactctgaat tatcttcttc atgttcatcc ctcatcttta 6360 ttgttactgg tttcatttcc cttggccaca tagcccacta ttttgtattc cccaatggat 6420 attgttcctt acaaagttca gccagggctc agaagtacaa ggaattggct cttatacttc 6480 tgtcagacag gcaaaaactt ctaaaattat actataataa aaatcaaaga gatgatattc 6540 ataattaaac taacaaaagt ggcaggcccc ccctccccca acatgagtag aattaatctg 6600 acgtccatgt tcaagtctga aacacacttg ccaattaaga gcacattagg gccagccttt 6660 atctccctct tagttactaa tgtgcagttc aatggtgagc tatagagaag gaagccaaga 6720 ctaccatatg tcaaatataa aaaaaaaaaa tcccatttta aatctgtagt cccgaattaa 6780 ggacaagaga gagggaaata tctttgacat tagaaaatgg agaaaatatt ttagcacagg 6840 actttactca gtcacatcag agttgataag tacgtatgac atccctcttt ttcctgtttt 6900 cctgagaaaa tgatctctct agtgtttcat ttaagataag tttattgaat taaactcagt 6960 aaatgaaaca actgacatga ctggagcttg aaataaacga tgtgatgatc tactgaaata 7020 catgatgcta aattgtcttg cttcttatgc aaaaactact attagttata gcaatgcatg 7080 gataattaag gccaaaaata tattagatgt taaaaatagt tttatattta tacatctgaa 7140 ttttaattta tatttaaagt atattggtcc aatcaattca tgcccaaatg ttttagttct 7200 attctttgag atactgtttt gttttgggat ttttttttat gagctaatct cttgcctagg 7260 agttcctact tctctctcct ccttttattt tttctaataa actacacatg tgtcttcatc 7320 caggagctaa cttctcccat tttgcttttc ctttagcacc ttttttatat tagatttctt 7380 tcttttctcc atctctttgc atattgccta tatttctttt cctaagcata atatttaaaa 7440 aagactgagt tttatgttaa gattatttct gctttgctct tacacagata ggataagtag 7500 tcttgataga aaataaatca atgattccta gggggatgtc tttttgcttt taatcaataa 7560 ggattctgac ttctctttct ctccatttgt gtattag 7597 <210> 15 <211> 282 <212> DNA <213> Mus musculus <400> 15 gtggttgtga atgccctgtt aggagcaatt ccatccatca tgaatgtgct tctggtttgc 60 cttatattct ggctaatttt cagcatcatg ggcgtaaatt tgtttgctgg caaattctac 120 cactgtgtta acaccacaac tggtgacata tttgagatca gcgaagtcaa taatcattct 180 gattgcctaa aactaataga aagaaatgag accgcccggt ggaaaaatgt gaaagtaaac 240 tttgataatg taggatttgg gtatctttct ttgcttcaag tt 282 <210> 16 <211> 64 <212> DNA <213> Mus musculus <400> 16 gataatcttg ctccaacttg gatggggtgg agcggtggtt cctcccctca gccctttatt 60 atgg 64 <210> 17 <211> 123 <212> RNA <213> Mus musculus <400> 17 guuucauugg ucaguuuaac agcaaaugcc uuggguuacu cugaacucgg ggccaucaaa 60 ucccuaagga cacuaagagc ucugagaccc cuaagagccu uaucacgauu ugaagggaug 120 agg 123 <210> 18 <211> 7597 <212> RNA <213> Mus musculus <400> 18 guaagaaaaa ggaaaacucu gcagcguugu auauugucaa agcuaggcug aguucaacuu 60 aacuaacgaa aaacacgugc augcaaaagg aauggcaacc cuuugcaaac uugcuacuuu 120 acccuuuucu cuguugcaua uuuacuucuu ggugauaugc aagagaaaau cggccucuuu 180 gaaaaugauu uaauaucauu uaucugcuuu gcuaauuaaa augaccuuag uucauaaucg 240 aucuugggag uuuccuuaua auuccuaaua caaaggggga ggggcagaua cucucuuaaa 300 gaacuaaguu gagucaugua auaauuaccu agagauaauu uuguuucaua ucguucuccu 360 cuaugacagc ccaucaguac uuaagggauc cuauggaaag uaaugugaau cacaaaugug 420 uaugaauaca aaggaaaaaa ugaagaauug uuaaauguuu ugucuuuaca augccaaaau 480 ucucauuauu ugaauauauc caagggcaga uauuaaccau ugacuggagu auaauaauac 540 ugccucaacu guaacuaaau uaaugacauu gaauaaguaa gacacuaauu uaauuacuau 600 aaauacauac acaucuuaug acaauacagc ugauaaggaa aaagaacaug uauuuuuauu 660 cauugccaua cauggcucgu caaccuuaac uuaaaccucg guucucaguu acacagaguu 720 uuauguugcu cuuuugagca aagcauuauu ccccucucca uaauucaaca cguaucagau 780 uuuugcauuu auuggcucau uguuaugaug auuauuucaa agcauuauac aaucauuuau 840 agaagaugug ccgugugaaa auuauuuuuu uauuaagauc caaaauuuac gcucuuuaaa 900 ccaaucagau gaaauguaua aggcaaagag ugcucauugu ccugacacuu acaaaccaag 960 gcuccaacaa acaggcuccu cucugcacca cauagagggc uuucagccug ugucccccca 1020 uaaaaaccua uuauaaauuu uauuauacua uacuguaaga aaccugucca auuuuuaauu 1080 ucucuagcac auaugaaaac uucucuucag uagauccaag uaagcacaaa ggagcuuuga 1140 uucucacaca agaaaucaca uuuguauuaa aaauguauca uaaauuuucu cccaauuaug 1200 caaaacuuaa augcuuuucc aauuaaaaga gcacuuucgu uucagaauag caauuucagu 1260 ugucaaggaa aacauuguuu uuauacauuu uauauaaaaa uacaugagcu aaauuuaaau 1320 ucacauuuuu caacuuuuua ugguuuuuuu auguuucuuu uucuuucgca uuuuuuaaca 1380 auccagccau uaccucuccu cccugucccc cuccuauagu uucucaucuc auuccuccuc 1440 ccccuugccu cugagaggau gcucccuccc ucacuaggcc ucccucuucc ccagggcuuc 1500 aaguuccuca aggauuauac acaucuucuc ccacugagac caggccaggc aguccucugc 1560 uucugcccag ccuguguaug uuccugcuug guagcucagu cucuggaagc ucccuggggu 1620 cuggguuagu ugggacugcu ggucuuccua uggaguuacc cuccccuuca acuucuucaa 1680 uccuuccccu aauucaacca cagguaucca gacuucaguc caaugguuga guguaaauau 1740 uggcaucugu cucugucagc uguuguuagg ggcucagagg acagccaugc uaggcuccug 1800 ccuacaagca gcacaccaua acaucaguaa uagugucagg ccuuuaauga auaaugcuac 1860 guauauaagg uuguuagauu auacuucaac uuugaucuuu uagaauauua uuaaauccag 1920 ucguuuauuu uuuauaugua auauugacuu uccauaacaa augagucuau uuuccuuuug 1980 uguagaaaua acuuuaucaa uuauuguuaa uaaugcuuuu gucaauuauu guugauaugc 2040 uucucuuuuu uaaaacugga gucaucaaaa caaaaauucu ggguagauau uacgaagcug 2100 acuccuuggu cagcuuggca cauagugaga ccacaaauau cucaagguca cggcaauucc 2160 ucaccaccag uuuggcauug ugaagucaaa accaaccuuc uguugauucu gguuuuugua 2220 uuucuaguau gagacauuuu cuacuuugua agaguauaua acuguggaug gcggcgaggu 2280 ugggcaugau gaugauugua agcgggaagu gagcuagagu aucuucagaa acucucacuu 2340 uauccuccuu ggcagcauag aaccgcaauc gcuguguccg agugucaacc aggcagucau 2400 uuuguuuugg guuuuuuguc acucuuucaa agcaugugcu ucuacgcaac acuaccaaac 2460 acagcaugcu gcauagugcu ugagaaggag uuagaaagua acaaacgagu uaucaucacg 2520 uugcccuuug uguuuugcau gucuuaugca cacuuuuggc ugacagcuuu ugaacauuua 2580 uuguauuuca aauuuccagu ccaaauuuuu uuuucaacuu gugaaauuga acggaaugaa 2640 ccgaugucgu gaauaccuag ggucaaauaa aacuuguauu uaaauucgua guuuuaauuu 2700 cccaagcugg gaaaaucgua aaaaccuuuu ccaaagaacu caagucuuag uugcuaggga 2760 aacaggcagu gagcaucaua uacaaaaagu aacaccaaau guucugucau aucagcuuuc 2820 uaacuaauaa uaaacuauau auuucuauuu uauauaggau aaucuugcuc caacuuggau 2880 gggguggagc ggugguuccu ccccucagcc cuuuauuaug gguacuguau uaccccuuuu 2940 gcuaccuuua auccuugcac ugugacuuau guguaguggg auugagggag ggagugggaa 3000 ggguacaauu gcaccacagu agggacaaua caggauuuau uuccaaaucc acuacuuuua 3060 augagcuuaa acuucuuuug ggaaaaaaaa aguuaucucu gacuuaccau cuguggauua 3120 uaaccccaga aguacauauc uuuauuacgu uucacugaau augauuuagc uauuuauacu 3180 ucauugucca uuuaugggga aauuacucaa uuggugaggg ugggggaccc ugguguagga 3240 ugcugaugaa aacguuuuca uuugucaagc ucaugguagu gacagagcau auaguccuua 3300 uuuuuucaac acacugcucu ggucccucaa ugggccaguc acauuccauc aguugaucgu 3360 ugaugugugc gagcaguggc uaaagguaca acaggccagg uaucucaggg uugccaaugg 3420 uuaugaucau ucucaucuuu auugcauaaa aauguguuau uugcagaaag uagcaaggca 3480 agaucccugu gaaacaaggg aauacaaaaa aaaaaaaaga ugugcuuuaa guuauaaaac 3540 caaaacaugu gaaaagucaa cuucauugaa guauaaagaa uaggauaugc augaaaaaca 3600 aaaaaaucau gagcacuaag aaauuggugu auaagccaac uccuuguaag cuaccccaau 3660 uaacuuccca gaaucuuaga aggcaucaca gugcacccca aaauaaaaag ccaaacugac 3720 acuucugcuu ccucuuaaaa uguaggaguc uuggauaaga aagauaauuu uuauuguuug 3780 gaagaaaaaa aaauuguuug gauaauugag gcauuuaucu aucaaaaaua uuuaucuuaa 3840 uaaaauuuca caacacugau uuaguuguug gcuuuucuaa aaauuuuuua uauuucauau 3900 uaagaacuca ugauuuuuac uuuccauuuu uuaaauucuu auucacauau gguuuuucuc 3960 uauuucuuag aaaagcuaua gaacccaugg uuuccgguga cuuaaaaaac uaaucuaaau 4020 gucuucacuu agaugauacu uucaaaugca cugaaauuuc uaauaucaac aagaauauuu 4080 gccugguccu aauuuuucac ugauuuaaua aaaaguauga acccuaaaga agaaauagac 4140 uugaagaacu gguuguguga caauacagaa auucugcugg gagauguccu uuuaaaacau 4200 uguuagaaga gacaaccucu acaauccacc cauuaagcau acuucucucu uagacaucuc 4260 cuuuuaugua ccuuauaacc ucaauguguu cuuuccaauu gacuuagacc aacacuuccc 4320 agcgcauccc acaugggagc caauuacuga cucucccuag agacugcaaa gaauuaauau 4380 uguagaacca agggaugguu gggcucuugg gagaggcaau ccguuuguga ucuuuugcuc 4440 uggauguuaa ugaaaucgca acuuuaagug gauuuucagu ggcaaauccu cugauccuau 4500 gccaaauguu cucuaagaca aacauccuug uaaaauaaau gucucacugg gccaaaucua 4560 uggcaaauuu gcacguuuuc cugaacugca uuccuauaua guauuugcca uccugaauuc 4620 acuaaugggc auuacuuuua auucaaaacc agucccuucu ucaaaggaaa ucucucccau 4680 uuauuacauu augcaaacug cuuucuuaug cagugguuaa auccuuagcc aggcaaguau 4740 gaggacugga auuuggauau ccagaacccu cagaaauguc ggaugggcau aguagcuuac 4800 auguaauucc agagcuagaa agaugaaacu agcccugucc ucaagcucug aauucaguug 4860 gugcaauaaa uaagaaagaa uccccccccc cgaccccuac aucucuuucc ucuacaucua 4920 uacauguauu ucccauacag cucuaugcuu ccacauauau gcucacauau gugcaugcac 4980 acuugcacac auauguacac uugacacauu gaagcaucau aaucuaacaa uuggaauaua 5040 agaaaauauu uaacuuucac acagagcagu cagagaaaac cauaagaggu ugaaacucuu 5100 gaaaaaacuu gcaggauaaa cagaaaagag uaugagaugc caauucuggu cuacuuucug 5160 aaccuaacuu guuuuaccuu cauuagucua auuuuccaaa ugaaccccaa gcaccaaauu 5220 guccuuauug cucuuuccag uacuaaauua uaauuccuca auucgaaggc aaacacucuc 5280 aucuuuguua aggaugugua gaguuagacu caauaaacga cauguauauu ugagcuaaag 5340 ccuggaggag ggagauuauu ucaagggcaa guacuuggca gggaguuuca aagaaagaag 5400 gcucucaauu cucagacuaa caccuuagcg uggagugacu gucacagagg agggugaagu 5460 guaugucacc aguuagggaa gcugaaaggg gaaauguauc aggcuuguga gaauccuuca 5520 gcagccaagu cuagcaccug agcacaaucc ccagaacuga ccccacaugg uggaaaggag 5580 aggaauaauu ccugcaaauu uuccugugac cuccacccaa gugcuauaga aaaugcaugc 5640 augcccacau gcacacacaa auaaacauag uugcaaacug uuuugaggaa aauaaccuca 5700 caaacugucg agugauguaa augccaaaga aagagaaaug uuuucuaaug gcuagagaac 5760 cauuaaggaa uuuuucaaaa ugggacaugg gauagauaaa uuuaguaucc auacugaaag 5820 aaggcaagca aauaaaaucu gauaagaaug uaauucuuag uaaccgagga cagagcgaag 5880 auagagaaca gggccaaugg ccaaggugga aagguuugaa ggaagcagca ugaaaccuac 5940 agacuuguac caaaauguuc agugucauga guguuaaaag ugaaaagcuu gcauguuagu 6000 auggauuuca uauccucggc agacagagca ccucacugug agugggagau gaaguauuca 6060 gaaaugagaa acaacuacuc aauuucagug uucauaucuc aaauccaaua aacaacuuua 6120 gggguacaau uuuuuaaaaa auuacauuaa aauguuuuua aaucucuucu uaauaauuua 6180 aaaauuaaau ugaaaauaac uuuaaaaagu aauauauaca ggaaagccug ugugcuaauu 6240 uuuuagggag gccauaaagg gagauaguug cucauuaauu ucuacacauc agccuaucuu 6300 uggcuucugc cuugauagcg cacucugaau uaucuucuuc auguucaucc cucaucuuua 6360 uuguuacugg uuucauuucc cuuggccaca uagcccacua uuuuguauuc cccaauggau 6420 auuguuccuu acaaaguuca gccagggcuc agaaguacaa ggaauuggcu cuuauacuuc 6480 ugucagacag gcaaaaacuu cuaaaauuau acuauaauaa aaaucaaaga gaugauauuc 6540 auaauuaaac uaacaaaagu ggcaggcccc cccuccccca acaugaguag aauuaaucug 6600 acguccaugu ucaagucuga aacacacuug ccaauuaaga gcacauuagg gccagccuuu 6660 aucucccucu uaguuacuaa ugugcaguuc aauggugagc uauagagaag gaagccaaga 6720 cuaccauaug ucaaauauaa aaaaaaaaaa ucccauuuua aaucuguagu cccgaauuaa 6780 ggacaagaga gagggaaaua ucuuugacau uagaaaaugg agaaaauauu uuagcacagg 6840 acuuuacuca gucacaucag aguugauaag uacguaugac aucccucuuu uuccuguuuu 6900 ccugagaaaa ugaucucucu aguguuucau uuaagauaag uuuauugaau uaaacucagu 6960 aaaugaaaca acugacauga cuggagcuug aaauaaacga ugugaugauc uacugaaaua 7020 caugaugcua aauugucuug cuucuuaugc aaaaacuacu auuaguuaua gcaaugcaug 7080 gauaauuaag gccaaaaaua uauuagaugu uaaaaauagu uuuauauuua uacaucugaa 7140 uuuuaauuua uauuuaaagu auauuggucc aaucaauuca ugcccaaaug uuuuaguucu 7200 auucuuugag auacuguuuu guuuugggau uuuuuuuuau gagcuaaucu cuugccuagg 7260 aguuccuacu ucucucuccu ccuuuuauuu uuucuaauaa acuacacaug ugucuucauc 7320 caggagcuaa cuucucccau uuugcuuuuc cuuuagcacc uuuuuuauau uagauuucuu 7380 ucuuuucucc aucucuuugc auauugccua uauuucuuuu ccuaagcaua auauuuaaaa 7440 aagacugagu uuuauguuaa gauuauuucu gcuuugcucu uacacagaua ggauaaguag 7500 ucuugauaga aaauaaauca augauuccua gggggauguc uuuuugcuuu uaaucaauaa 7560 ggauucugac uucucuuucu cuccauuugu guauuag 7597 <210> 19 <211> 282 <212> RNA <213> Mus musculus <400> 19 gugguuguga augcccuguu aggagcaauu ccauccauca ugaaugugcu ucugguuugc 60 cuuauauucu ggcuaauuuu cagcaucaug ggcguaaauu uguuugcugg caaauucuac 120 cacuguguua acaccacaac uggugacaua uuugagauca gcgaagucaa uaaucauucu 180 gauugccuaa aacuaauaga aagaaaugag accgcccggu ggaaaaaugu gaaaguaaac 240 uuugauaaug uaggauuugg guaucuuucu uugcuucaag uu 282 <210> 20 <211> 64 <212> RNA <213> Mus musculus <400> 20 gauaaucuug cuccaacuug gauggggugg agcggugguu ccuccccuca gcccuuuauu 60 augg 64 <210> 21 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 21 gatgctctcc gtctgttt 18 <210> 22 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 22 ttcatgatgc tctccgtc 18 <210> 23 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 23 ttttgttcat gatgctct 18 <210> 24 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 24 ttactttttg ttcatgat 18 <210> 25 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 25 tggtgttact ttttgttc 18 <210> 26 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 26 acatttggtg ttactttt 18 <210> 27 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 27 acagaacatt tggtgtta 18 <210> 28 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 28 atatgacaga acatttgg 18 <210> 29 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 29 atctgatatg acagaaca 18 <210> 30 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 30 tagaaatctg atatgaca 18 <210> 31 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 31 ttagttagaa atctgata 18 <210> 32 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 32 tgttattagt tagaaatc 18 <210> 33 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 33 tagtttgtta ttagttag 18 <210> 34 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 34 atatatagtt tgttatta 18 <210> 35 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 35 tagaaatata tagtttgt 18 <210> 36 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 36 caaaatagaa atatatag 18 <210> 37 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 37 atacaaaata gaaatata 18 <210> 38 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 38 ctatacaaaa tagaaata 18 <210> 39 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 39 tcctatacaa aatagaaa 18 <210> 40 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 40 tatcctatac aaaataga 18 <210> 41 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 41 attatcctat acaaaata 18 <210> 42 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 42 agttggagca agattatc 18 <210> 43 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 43 atccaagttg gagcaaga 18 <210> 44 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 44 accccatcca agttggag 18 <210> 45 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 45 gctccacccc atccaagt 18 <210> 46 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 46 ccagcgctcc accccatc 18 <210> 47 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 47 gaaccagcgc tccacccc 18 <210> 48 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 48 gggaggaacc agcgctcc 18 <210> 49 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 49 ataataaagg gctcaggg 18 <210> 50 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 50 ccataataaa gggctcag 18 <210> 51 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 51 gtaatacagt acccataa 18 <210> 52 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 52 gggtaataca gtacccat 18 <210> 53 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 53 ttaaaggtag caaaaggg 18 <210> 54 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 54 aaggattaaa ggtagcaa 18 <210> 55 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 55 agtgcaagga ttaaaggt 18 <210> 56 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 56 gtcacagtgc aaggatta 18 <210> 57 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 57 cataagtcac agtgcaag 18 <210> 58 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 58 ctacacataa gtcacagt 18 <210> 59 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 59 ccccactaca cataagtc 18 <210> 60 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 60 cctcacccca ctacacat 18 <210> 61 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 61 ccctccctca ccccacta 18 <210> 62 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 62 ccaatccctc cctcaccc 18 <210> 63 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 63 ccttcccaat ccctccct 18 <210> 64 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 64 agtacccttc ccaatccc 18 <210> 65 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 65 ataatagtac ccttccca 18 <210> 66 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 66 gtgcaataat agtaccct 18 <210> 67 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 67 ctgtggtgca ataatagt 18 <210> 68 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 68 gatgctcact gcctgttt 18 <210> 69 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 69 tatatgatgc tcactgcc 18 <210> 70 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 70 ttttgtatat gatgctca 18 <210> 71 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 71 ttactttttg tatatgat 18 <210> 72 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 72 tggtgttact ttttgtat 18 <210> 73 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 73 acatttggtg ttactttt 18 <210> 74 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 74 acagaacatt tggtgtta 18 <210> 75 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 75 atatgacaga acatttgg 18 <210> 76 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 76 agctgatatg acagaaca 18 <210> 77 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 77 tagaaagctg atatgaca 18 <210> 78 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 78 ttagttagaa agctgata 18 <210> 79 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 79 tattattagt tagaaagc 18 <210> 80 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 80 tagtttatta ttagttag 18 <210> 81 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 81 atatatagtt tattatta 18 <210> 82 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 82 tagaaatata tagtttat 18 <210> 83 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 83 taaaatagaa atatatag 18 <210> 84 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 84 atataaaata gaaatata 18 <210> 85 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 85 ctatataaaa tagaaata 18 <210> 86 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 86 tcctatataa aatagaaa 18 <210> 87 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 87 tatcctatat aaaataga 18 <210> 88 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 88 attatcctat ataaaata 18 <210> 89 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 89 agttggagca agattatc 18 <210> 90 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 90 atccaagttg gagcaaga 18 <210> 91 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 91 accccatcca agttggag 18 <210> 92 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 92 gctccacccc atccaagt 18 <210> 93 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 93 ccaccgctcc accccatc 18 <210> 94 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 94 gaaccaccgc tccacccc 18 <210> 95 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 95 gggaggaacc accgctcc 18 <210> 96 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 96 ataataaagg gctgaggg 18 <210> 97 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 97 ccataataaa gggctgag 18 <210> 98 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 98 gtaatacagt acccataa 18 <210> 99 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 99 gggtaataca gtacccat 18 <210> 100 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 100 ttaaaggtag caaaaggg 18 <210> 101 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 101 aaggattaaa ggtagcaa 18 <210> 102 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 102 agtgcaagga ttaaaggt 18 <210> 103 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 103 gtcacagtgc aaggatta 18 <210> 104 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 104 cataagtcac agtgcaag 18 <210> 105 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 105 ctacacataa gtcacagt 18 <210> 106 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 106 tcccactaca cataagtc 18 <210> 107 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 107 ctcaatccca ctacacat 18 <210> 108 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 108 cctccctcaa tcccacta 18 <210> 109 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 109 cactccctcc ctcaatcc 18 <210> 110 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 110 cttcccactc cctccctc 18 <210> 111 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 111 gtacccttcc cactccct 18 <210> 112 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 112 caattgtacc cttcccac 18 <210> 113 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 113 tggtgcaatt gtaccctt 18 <210> 114 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 114 tactgtggtg caattgta 18 <210> 115 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 115 cagagaaaau aguguuca 18 <210> 116 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 116 auauucagag aaaauagu 18 <210> 117 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 117 uaaaaauauu cagagaaa 18 <210> 118 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 118 aacaauaaaa auauucag 18 <210> 119 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 119 uuccaaacaa uaaaaaua 18 <210> 120 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 120 uauuauucca aacaauaa 18 <210> 121 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 121 uuuguuauua uuccaaac 18 <210> 122 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 122 auuauuuugu uauuauuc 18 <210> 123 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 123 augucauuau uuuguuau 18 <210> 124 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 124 gauguauguc auuauuuu 18 <210> 125 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 125 uaauagaugu augucauu 18 <210> 126 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 126 cuaaauaaua gauguaug 18 <210> 127 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 127 aggaacuaaa uaauagau 18 <210> 128 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 128 uucuuaggaa cuaaauaa 18 <210> 129 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 129 acuuuuucuu aggaacua 18 <210> 130 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 130 uauauacuuu uucuuagg 18 <210> 131 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 131 ugcauguuuu acuuugga 18 <210> 132 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 132 guuuuacuuu ggaguaaa 18 <210> 133 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 133 acuuuggagu aaaaauaa 18 <210> 134 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 134 ggaguaaaaa uaauuuag 18 <210> 135 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 135 aaaaauaauu uagaccug 18 <210> 136 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 136 uaauuuagac cugauguu 18 <210> 137 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 137 uagaccugau guuuaaua 18 <210> 138 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 138 cugauguuua auaaauau 18 <210> 139 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 139 guuuaauaaa uauucuua 18 <210> 140 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 140 auaaauauuc uuacugau 18 <210> 141 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 141 uauucuuacu gauauaau 18 <210> 142 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 142 uuacugauau aauuuuca 18 <210> 143 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 143 gauauaauuu ucaaaagg 18 <210> 144 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 144 aauuuucaaa agggaaua 18 <210> 145 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 145 cuuuggagua aaaauaau 18 <210> 146 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 146 uuuggaguaa aaauaauu 18 <210> 147 <400> 147 000 <210> 148 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 148 uuggaguaaa aauaauuu 18 <210> 149 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 149 uggaguaaaa auaauuua 18 <210> 150 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 150 gaguaaaaau aauuuaga 18 <210> 151 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 151 aguaaaaaua auuuagac 18 <210> 152 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 152 guaaaaauaa uuuagacc 18 <210> 153 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 153 uaaaaauaau uuagaccu 18 <210> 154 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 154 uacugauaua auuuucaa 18 <210> 155 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 155 acugauauaa uuuucaaa 18 <210> 156 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 156 cugauauaau uuucaaaa 18 <210> 157 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 157 ugauauaauu uucaaaag 18 <210> 158 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 158 auauaauuuu caaaaggg 18 <210> 159 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 159 uauaauuuuc aaaaggga 18 <210> 160 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 160 auaauuuuca aaagggaa 18 <210> 161 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 161 uaauuuucaa aagggaau 18 <210> 162 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 162 caaggauuaa agguagca 18 <210> 163 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 163 cagagaaaat agtgttca 18 <210> 164 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 164 atattcagag aaaatagt 18 <210> 165 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 165 taaaaatatt cagagaaa 18 <210> 166 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 166 aacaataaaa atattcag 18 <210> 167 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 167 ttccaaacaa taaaaata 18 <210> 168 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 168 tattattcca aacaataa 18 <210> 169 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 169 tttgttatta ttccaaac 18 <210> 170 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 170 attattttgt tattattc 18 <210> 171 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 171 atgtcattat tttgttat 18 <210> 172 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 172 gatgtatgtc attatttt 18 <210> 173 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 173 taatagatgt atgtcatt 18 <210> 174 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 174 ctaaataata gatgtatg 18 <210> 175 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 175 aggaactaaa taatagat 18 <210> 176 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 176 ttcttaggaa ctaaataa 18 <210> 177 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 177 actttttctt aggaacta 18 <210> 178 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 178 tatatacttt ttcttagg 18 <210> 179 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 179 tgcatgtttt actttgga 18 <210> 180 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 180 gttttacttt ggagtaaa 18 <210> 181 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 181 actttggagt aaaaataa 18 <210> 182 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 182 ggagtaaaaa taatttag 18 <210> 183 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 183 aaaaataatt tagacctg 18 <210> 184 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 184 taatttagac ctgatgtt 18 <210> 185 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 185 tagacctgat gtttaata 18 <210> 186 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 186 ctgatgttta ataaatat 18 <210> 187 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 187 gtttaataaa tattctta 18 <210> 188 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 188 ataaatattc ttactgat 18 <210> 189 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 189 tattcttact gatataat 18 <210> 190 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 190 ttactgatat aattttca 18 <210> 191 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 191 gatataattt tcaaaagg 18 <210> 192 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 192 aattttcaaa agggaata 18 <210> 193 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 193 ctttggagta aaaataat 18 <210> 194 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 194 tttggagtaa aaataatt 18 <210> 195 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 195 ttggagtaaa aataattt 18 <210> 196 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 196 tggagtaaaa ataattta 18 <210> 197 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 197 gagtaaaaat aatttaga 18 <210> 198 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 198 agtaaaaata atttagac 18 <210> 199 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 199 gtaaaaataa tttagacc 18 <210> 200 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 200 taaaaataat ttagacct 18 <210> 201 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 201 tactgatata attttcaa 18 <210> 202 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 202 actgatataa ttttcaaa 18 <210> 203 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 203 ctgatataat tttcaaaa 18 <210> 204 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 204 tgatataatt ttcaaaag 18 <210> 205 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 205 atataatttt caaaaggg 18 <210> 206 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 206 tataattttc aaaaggga 18 <210> 207 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 207 ataattttca aaagggaa 18 <210> 208 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 208 taattttcaa aagggaat 18 <210> 209 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 209 caaggattaa aggtagca 18 <210> 210 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 210 gaugcucucc gucuguuu 18 <210> 211 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 211 uucaugaugc ucuccguc 18 <210> 212 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 212 uuuuguucau gaugcucu 18 <210> 213 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 213 uuacuuuuug uucaugau 18 <210> 214 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 214 ugguguuacu uuuuguuc 18 <210> 215 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 215 acauuuggug uuacuuuu 18 <210> 216 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 216 acagaacauu ugguguua 18 <210> 217 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 217 auaugacaga acauuugg 18 <210> 218 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 218 aucugauaug acagaaca 18 <210> 219 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 219 uagaaaucug auaugaca 18 <210> 220 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 220 uuaguuagaa aucugaua 18 <210> 221 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 221 uguuauuagu uagaaauc 18 <210> 222 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 222 uaguuuguua uuaguuag 18 <210> 223 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 223 auauauaguu uguuauua 18 <210> 224 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 224 uagaaauaua uaguuugu 18 <210> 225 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 225 caaaauagaa auauauag 18 <210> 226 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 226 auacaaaaua gaaauaua 18 <210> 227 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 227 cuauacaaaa uagaaaua 18 <210> 228 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 228 uccuauacaa aauagaaa 18 <210> 229 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 229 uauccuauac aaaauaga 18 <210> 230 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 230 auuauccuau acaaaaua 18 <210> 231 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 231 aguuggagca agauuauc 18 <210> 232 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 232 auccaaguug gagcaaga 18 <210> 233 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 233 accccaucca aguuggag 18 <210> 234 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 234 gcuccacccc auccaagu 18 <210> 235 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 235 ccagcgcucc accccauc 18 <210> 236 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 236 gaaccagcgc uccacccc 18 <210> 237 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 237 gggaggaacc agcgcucc 18 <210> 238 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 238 auaauaaagg gcucaggg 18 <210> 239 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 239 ccauaauaaa gggcucag 18 <210> 240 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 240 guaauacagu acccauaa 18 <210> 241 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 241 ggguaauaca guacccau 18 <210> 242 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 242 uuaaagguag caaaaggg 18 <210> 243 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 243 aaggauuaaa gguagcaa 18 <210> 244 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 244 agugcaagga uuaaaggu 18 <210> 245 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 245 gucacagugc aaggauua 18 <210> 246 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 246 cauaagucac agugcaag 18 <210> 247 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 247 cuacacauaa gucacagu 18 <210> 248 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 248 ccccacuaca cauaaguc 18 <210> 249 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 249 ccucacccca cuacacau 18 <210> 250 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 250 cccucccuca ccccacua 18 <210> 251 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 251 ccaaucccuc ccucaccc 18 <210> 252 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 252 ccuucccaau cccucccu 18 <210> 253 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 253 aguacccuuc ccaauccc 18 <210> 254 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 254 auaauaguac ccuuccca 18 <210> 255 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 255 gugcaauaau aguacccu 18 <210> 256 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 256 cuguggugca auaauagu 18 <210> 257 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 257 gaugcucacu gccuguuu 18 <210> 258 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 258 uauaugaugc ucacugcc 18 <210> 259 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 259 uuuuguauau gaugcuca 18 <210> 260 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 260 uuacuuuuug uauaugau 18 <210> 261 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 261 ugguguuacu uuuuguau 18 <210> 262 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 262 acauuuggug uuacuuuu 18 <210> 263 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 263 acagaacauu ugguguua 18 <210> 264 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 264 auaugacaga acauuugg 18 <210> 265 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 265 agcugauaug acagaaca 18 <210> 266 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 266 uagaaagcug auaugaca 18 <210> 267 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 267 uuaguuagaa agcugaua 18 <210> 268 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 268 uauuauuagu uagaaagc 18 <210> 269 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 269 uaguuuauua uuaguuag 18 <210> 270 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 270 auauauaguu uauuauua 18 <210> 271 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 271 uagaaauaua uaguuuau 18 <210> 272 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 272 uaaaauagaa auauauag 18 <210> 273 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 273 auauaaaaua gaaauaua 18 <210> 274 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 274 cuauauaaaa uagaaaua 18 <210> 275 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 275 uccuauauaa aauagaaa 18 <210> 276 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 276 uauccuauau aaaauaga 18 <210> 277 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 277 auuauccuau auaaaaua 18 <210> 278 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 278 aguuggagca agauuauc 18 <210> 279 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 279 auccaaguug gagcaaga 18 <210> 280 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 280 accccaucca aguuggag 18 <210> 281 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 281 gcuccacccc auccaagu 18 <210> 282 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 282 ccaccgcucc accccauc 18 <210> 283 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 283 gaaccaccgc uccacccc 18 <210> 284 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 284 gggaggaacc accgcucc 18 <210> 285 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 285 auaauaaagg gcugaggg 18 <210> 286 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 286 ccauaauaaa gggcugag 18 <210> 287 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 287 guaauacagu acccauaa 18 <210> 288 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 288 ggguaauaca guacccau 18 <210> 289 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 289 uuaaagguag caaaaggg 18 <210> 290 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 290 aaggauuaaa gguagcaa 18 <210> 291 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 291 agugcaagga uuaaaggu 18 <210> 292 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 292 gucacagugc aaggauua 18 <210> 293 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 293 cauaagucac agugcaag 18 <210> 294 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 294 cuacacauaa gucacagu 18 <210> 295 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 295 ucccacuaca cauaaguc 18 <210> 296 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 296 cucaauccca cuacacau 18 <210> 297 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 297 ccucccucaa ucccacua 18 <210> 298 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 298 cacucccucc cucaaucc 18 <210> 299 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 299 cuucccacuc ccucccuc 18 <210> 300 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 300 guacccuucc cacucccu 18 <210> 301 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 301 caauuguacc cuucccac 18 <210> 302 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 302 uggugcaauu guacccuu 18 <210> 303 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 303 uacuguggug caauugua 18 <210> 304 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 304 ttggagcaag attatc 16 <210> 305 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 305 gttggagcaa gattatc 17 <210> 306 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 306 gttggagcaa gattat 16 <210> 307 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 307 agttggagca agattat 17 <210> 308 <211> 16 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 308 agttggagca agatta 16 <210> 309 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 309 gattatccta tacaaaat 18 <210> 310 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 310 agattatcct atacaaaa 18 <210> 311 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 311 aagattatcc tatacaaa 18 <210> 312 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 312 caagattatc ctatacaa 18 <210> 313 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 313 gcaagattat cctataca 18 <210> 314 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 314 agcaagatta tcctatac 18 <210> 315 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 315 gagcaagatt atcctata 18 <210> 316 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 316 ggagcaagat tatcctat 18 <210> 317 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 317 tggagcaaga ttatccta 18 <210> 318 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 318 gttggagcaa gattatcc 18 <210> 319 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 319 ttggagcaag attatcct 18 <210> 320 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 320 aagttggagc aagattat 18 <210> 321 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 321 caagttggag caagatta 18 <210> 322 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 322 ccaagttgga gcaagatt 18 <210> 323 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 323 tccaagttgg agcaagat 18 <210> 324 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 324 agtacccata ataaaggg 18 <210> 325 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 325 aatacagtac ccataata 18 <210> 326 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 326 attaaaggta gcaaaagg 18 <210> 327 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 327 gattaaaggt agcaaaag 18 <210> 328 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 328 ggattaaagg tagcaaaa 18 <210> 329 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 329 aggattaaag gtagcaaa 18 <210> 330 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 330 caaggattaa aggtagca 18 <210> 331 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 331 gcaaggatta aaggtagc 18 <210> 332 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 332 tgcaaggatt aaaggtag 18 <210> 333 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 333 gtgcaaggat taaaggta 18 <210> 334 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 334 agtcacagtg caaggatt 18 <210> 335 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 335 aagtcacagt gcaaggat 18 <210> 336 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 336 taagtcacag tgcaagga 18 <210> 337 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 337 ataagtcaca gtgcaagg 18 <210> 338 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 338 acataagtca cagtgcaa 18 <210> 339 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 339 cacataagtc acagtgca 18 <210> 340 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 340 acacataagt cacagtgc 18 <210> 341 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 341 tacacataag tcacagtg 18 <210> 342 <211> 16 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 342 uuggagcaag auuauc 16 <210> 343 <211> 17 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 343 guuggagcaa gauuauc 17 <210> 344 <211> 16 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 344 guuggagcaa gauuau 16 <210> 345 <211> 17 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 345 aguuggagca agauuau 17 <210> 346 <211> 16 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 346 aguuggagca agauua 16 <210> 347 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 347 gauuauccua uacaaaau 18 <210> 348 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 348 agauuauccu auacaaaa 18 <210> 349 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 349 aagauuaucc uauacaaa 18 <210> 350 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 350 caagauuauc cuauacaa 18 <210> 351 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 351 gcaagauuau ccuauaca 18 <210> 352 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 352 agcaagauua uccuauac 18 <210> 353 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 353 gagcaagauu auccuaua 18 <210> 354 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 354 ggagcaagau uauccuau 18 <210> 355 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 355 uggagcaaga uuauccua 18 <210> 356 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 356 guuggagcaa gauuaucc 18 <210> 357 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 357 uuggagcaag auuauccu 18 <210> 358 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 358 aaguuggagc aagauuau 18 <210> 359 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 359 caaguuggag caagauua 18 <210> 360 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 360 ccaaguugga gcaagauu 18 <210> 361 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 361 uccaaguugg agcaagau 18 <210> 362 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 362 aguacccaua auaaaggg 18 <210> 363 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 363 aauacaguac ccauaaua 18 <210> 364 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 364 auuaaaggua gcaaaagg 18 <210> 365 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 365 gauuaaaggu agcaaaag 18 <210> 366 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 366 ggauuaaagg uagcaaaa 18 <210> 367 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 367 aggauuaaag guagcaaa 18 <210> 368 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 368 caaggauuaa agguagca 18 <210> 369 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 369 gcaaggauua aagguagc 18 <210> 370 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 370 ugcaaggauu aaagguag 18 <210> 371 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 371 gugcaaggau uaaaggua 18 <210> 372 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 372 agucacagug caaggauu 18 <210> 373 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 373 aagucacagu gcaaggau 18 <210> 374 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 374 uaagucacag ugcaagga 18 <210> 375 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 375 auaagucaca gugcaagg 18 <210> 376 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 376 acauaaguca cagugcaa 18 <210> 377 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 377 cacauaaguc acagugca 18 <210> 378 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 378 acacauaagu cacagugc 18 <210> 379 <211> 18 <212> RNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic oligonucleotide <400> 379 uacacauaag ucacagug 18 <210> 380 <211> 264 <212> DNA <213> Homo sapiens <400> 380 ggaaacagac ggagagcatc atgaacaaaa agtaacacca aatgttctgt catatcagat 60 ttctaactaa taacaaacta tatatttcta ttttgtatag gataatcttg ctccaacttg 120 gatggggtgg agcgctggtt cctcccctga gccctttatt atgggtactg tattacccct 180 tttgctacct ttaatccttg cactgtgact tatgtgtagt ggggtgaggg agggattggg 240 aagggtacta ttattgcacc acag 264 <210> 381 <211> 98 <212> DNA <213> Homo sapiens <400> 381 aaacagacgg agagcatcat gaacaaaaag taacaccaaa tgttctgtca tatcagattt 60 ctaactaata acaaactata tatttctatt ttgtatag 98 <210> 382 <211> 94 <212> DNA <213> Homo sapiens <400> 382 tttctatttt gtataggata atcttgctcc aacttggatg gggtggagcg ctggttcctc 60 ccctgagccc tttattatgg gtactgtatt accc 94 <210> 383 <211> 100 <212> DNA <213> Homo sapiens <400> 383 gtactgtatt accccttttg ctacctttaa tccttgcact gtgacttatg tgtagtgggg 60 tgagggaggg attgggaagg gtactattat tgcaccacag 100

Claims (77)

  1. SCN1A 단백질을 코딩하는, 넌센스 매개 RNA 붕괴 유도 엑손을 함유하는 mRNA(NMD 엑손 mRNA)를 갖는 세포에서 SCN1A 단백질의 발현을 조절하는 방법으로서, 치료제를 세포에 접촉시키는 단계를 포함하고, 그로 인하여 치료제가 SCN1A 단백질을 코딩하는 NMD 엑손 mRNA로부터 NMD 엑손의 스플라이싱을 조절하고, 이로써 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 조절하고, SCN1A 단백질의 발현을 조절하는 것인 방법.
  2. 치료를 필요로 하는 대상체의 세포에서 SCN1A 단백질의 발현을 조절함으로써 대상체에서 질환 또는 병태를 치료하는 방법으로서, 대상체의 세포를 넌센스 매개 mRNA 붕괴 유도 엑손(NMD 엑손)을 함유하고 SCN1A를 코딩하는 세포에서 mRNA로부터 NMD 엑손의 스플라이싱을 조절하는 치료제와 접촉시키는 단계를 포함하고, 그로 인하여 대상체의 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 조절하고, SCN1A 단백질의 발현을 조절하는 것인 방법.
  3. 제1항 또는 제2항에 있어서, 치료제는
    (a) SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 결합하거나;
    (b) NMD 엑손 mRNA의 스플라이싱에 관여하는 인자의 결합을 조절하거나;
    (c) (a)와 (b)의 조합인 방법.
  4. 제3항에 있어서, 치료제는 표적화된 부분의 영역으로부터 NMD 엑손의 스플라이싱에 관여하는 인자의 결합을 방해하는 것인 방법.
  5. 제3항에 있어서, 표적화된 부분은 NMD 엑손에 근접한 것인 방법.
  6. 제5항에 있어서, 표적화된 부분은 NMD 엑손의 5' 말단의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 상류에 있는 것인 방법.
  7. 제5항에 있어서, 표적화된 부분은 NMD 엑손의 5' 말단의 적어도 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 상류에 있는 것인 방법.
  8. 제5항에 있어서, 표적화된 부분은 NMD 엑손의 3' 말단의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 하류에 있는 것인 방법.
  9. 제5항에 있어서, 표적화된 부분은 NMD 엑손의 3' 말단의 적어도 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 하류에 있는 것인 방법.
  10. 제3항에 있어서, 표적화된 부분은 SCN1A를 코딩하는 NMD 엑손 mRNA의 2개의 표준 엑손 영역 사이의 인트론 영역에 위치하며, 인트론 영역은 NMD 엑손을 함유하는 것인 방법.
  11. 제3항에 있어서, 표적화된 부분은 NMD 엑손과 적어도 부분적으로 중첩되는 것인 방법.
  12. 제3항에 있어서, 표적화된 부분은 NMD 엑손의 상류 인트론과 적어도 부분적으로 중첩되는 것인 방법.
  13. 제3항에 있어서, 표적화된 부분은 5' NMD 엑손-인트론 접합부 또는 3' NMD 엑손-인트론 접합부를 포함하는 것인 방법.
  14. 제3항에 있어서, 표적화된 부분은 NMD 엑손 내에 있는 것인 방법.
  15. 제3항에 있어서, 표적화된 부분은 NMD 엑손의 약 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30개 또는 그 이상의 연속적인 뉴클레오티드를 포함하는 것인 방법.
  16. 제1항 또는 제2항에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA는 서열 번호 2 또는 7 내지 10 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함하는 것인 방법.
  17. 제1항 또는 제2항에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA는 서열 번호 1 또는 3 내지 6과 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 유전자 서열에 의해 코딩되는 것인 방법.
  18. 제5항에 있어서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,803의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 상류에 있는 것인 방법.
  19. 제5항에 있어서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,803의 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 상류에 있는 것인 방법.
  20. 제5항에 있어서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,740의 최대 약 1500 뉴클레오티드, 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드 하류에 있는 것인 방법.
  21. 제5항에 있어서, 표적화된 부분은 게놈 부위 GRCh37/hg19: chr2:166,863,740의 약 1000 뉴클레오티드, 약 800 뉴클레오티드, 약 700 뉴클레오티드, 약 600 뉴클레오티드, 약 500 뉴클레오티드, 약 400 뉴클레오티드, 약 300 뉴클레오티드, 약 200 뉴클레오티드, 약 100 뉴클레오티드, 약 80 뉴클레오티드, 약 70 뉴클레오티드, 약 60 뉴클레오티드, 약 50 뉴클레오티드, 약 40 뉴클레오티드, 약 30 뉴클레오티드, 약 20 뉴클레오티드, 약 10 뉴클레오티드, 약 5 뉴클레오티드, 약 4 뉴클레오티드, 약 2 뉴클레오티드, 약 1 뉴클레오티드 하류에 있는 것인 방법.
  22. 제3항에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 서열 번호 2 또는 7 내지 10의 적어도 8개의 인접한 핵산을 포함하는 영역과 적어도 80%, 85%, 90%, 95%, 97%, 또는 100% 서열 동일성을 갖는 서열을 포함하는 것인 방법.
  23. 제1항 또는 제2항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21 내지 67, 210 내지 256, 또는 304 내지 379 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
  24. 제3항에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x 내에 있는 것인 방법.
  25. 제24항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 42 내지 50, 또는 231 내지 239 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
  26. 제3항에 있어서, SCN1A를 코딩하는 NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 넌센스 매개 RNA 붕괴 유도 엑손 20x의 상류 또는 하류에 있는 것인 방법.
  27. 제26항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21 내지 38, 53 내지 67, 210 내지 227, 또는 242 내지 256 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
  28. 제3항에 있어서, NMD 엑손 mRNA의 표적화된 부분은 SCN1A의 엑손 20x의 엑손-인트론 접합부를 포함하는 것인 방법.
  29. 제28항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 39 내지 41, 51, 52, 228 내지 230, 240, 또는 241 중 어느 하나와 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 동일성인 서열을 포함하는 것인 방법.
  30. 제1항 또는 제2항에 있어서, 치료제는 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 촉진하는 것인 방법.
  31. 제30항에 있어서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제는 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제와 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가하는 것인 방법.
  32. 제30항에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 증가시키는 것인 방법.
  33. 제30항에 있어서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 양은 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가하는 것인 방법.
  34. 제30항에 있어서, 치료제는 세포에서 SCN1A 단백질의 발현을 증가시키는 것인 방법.
  35. 제30항에 있어서, 치료제와 접촉된 세포에서 생성된 SCN1A의 양은 대조군 세포에서 생성된 SCN1A의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 증가하는 것인 방법.
  36. 제2항에 있어서, 질환 또는 병태는 Nav1.1의 기능 상실 돌연변이에 의해 유발되는 것인 방법.
  37. 제36항에 있어서, 질환 또는 병태는 SCN1A 유전자의 반가불충분성과 관련되며, 대상체는 기능성 SCN1A를 코딩하는 제1 대립 유전자, 및 SCN1A가 생성되지 않거나 감소한 수준으로 생성되는 제2 대립 유전자, 또는 비기능성 SCN1A 또는 부분 기능성 SCN1A를 코딩하는 제2 대립 유전자를 갖는 것인 방법.
  38. 제36항에 있어서, 질환 또는 병태는 뇌병증인 방법.
  39. 제38항에 있어서, 뇌병증은 간질성 뇌병증인 방법.
  40. 제36항에 있어서, 질환 또는 병태는 드라벳 증후군(DS); 유아기의 중증 근간대성 뇌전증(SMEI) 경계성(SMEB); 열성 발작(FS); 열성 발작 플러스를 동반하는 전신 뇌전증(GEFS+); 조기 유아 간질성 뇌병증 13; 잠재성 전신 뇌전증; 잠재성 초점 뇌전증; 근간대성 무정위 뇌전증; 레녹스-가스토 증후군; 웨스트 증후군; 특발성 경련; 조기 근간대성 뇌병증; 진행성 근간대성 뇌전증; 소아기 교대성 편마비; 미분류 간질성 뇌병증; 뇌전증에서의 돌연사(SUDEP); 동기능 부전 증후군 1; 자폐증; 또는 유아기의 악성 이동 부분 발작인 방법.
  41. 제40항에 있어서, GEFS+는 열성 발작 플러스를 동반하는 전신 뇌전증 2형인 방법.
  42. 제40항에 있어서, 열성 발작은 가족성 열성 발작 3A인 방법.
  43. 제40항에 있어서, SMEB는 전신 극파가 없는 SMEB(SMEB-SW), 근간대성 발작이 없는 SMEB(SMEB-M), SMEI의 하나 초과의 특징이 결여된 SMEB(SMEB-O), 또는 전신 강직성 간대 발작을 동반한 난치성 소아기 뇌전증(ICEGTC)인 방법.
  44. 제36항에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 촉진하고 SCN1A의 발현을 증가시키는 것인 방법.
  45. 제36항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 22 내지 24, 26, 27, 29 내지 35, 37 내지 62, 64 내지 67, 또는 304 내지 379 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함하는 것인 방법.
  46. 제1항 또는 제2항에 있어서, 치료제는 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 억제하는 것인 방법.
  47. 제46항에 있어서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제는 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제와 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소하는 것인 방법.
  48. 제46항에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 수준을 감소시키는 것인 방법.
  49. 제46항에 있어서, 치료제와 접촉된 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 양은 대조군 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소하는 것인 방법.
  50. 제46항에 있어서, 치료제는 세포에서 SCN1A 단백질의 발현을 감소시키는 것인 방법.
  51. 제46항에 있어서, 치료제와 접촉된 세포에서 생성된 SCN1A의 양은 대조군 세포에서 생성된 SCN1A의 총량과 비교하여 약 1.1 내지 약 10배, 약 1.5 내지 약 10배, 약 2 내지 약 10배, 약 3 내지 약 10배, 약 4 내지 약 10배, 약 1.1 내지 약 5배, 약 1.1 내지 약 6배, 약 1.1 내지 약 7배, 약 1.1 내지 약 8배, 약 1.1 내지 약 9배, 약 2 내지 약 5배, 약 2 내지 약 6배, 약 2 내지 약 7배, 약 2 내지 약 8배, 약 2 내지 약 9배, 약 3 내지 약 6배, 약 3 내지 약 7배, 약 3 내지 약 8배, 약 3 내지 약 9배, 약 4 내지 약 7배, 약 4 내지 약 8배, 약 4 내지 약 9배, 적어도 약 1.1배, 적어도 약 1.5배, 적어도 약 2배, 적어도 약 2.5배, 적어도 약 3배, 적어도 약 3.5배, 적어도 약 4배, 적어도 약 5배, 또는 적어도 약 10배 감소하는 것인 방법.
  52. 제2항에 있어서, 질환 또는 병태는 Nav1.1의 기능 획득 돌연변이에 의해 유발되는 것인 방법.
  53. 제52항에 있어서, 대상체는 세포에서 SCN1A가 증가한 수준으로 생성되는 대립 유전자, 또는 Nav1.1의 증가한 활성을 유도하는 돌연변이 SCN1A를 코딩하는 대립 유전자를 갖는 것인 방법.
  54. 제52항에 있어서, 질환 또는 병태는 편두통인 방법.
  55. 제54항에 있어서, 편두통은 가족성 편마비 편두통 3인 방법.
  56. 제2항에 있어서, 질환 또는 병태는 Nav1.1 유전성 뇌전증인 방법.
  57. 제52항에 있어서, 치료제는 세포에서 SCN1A 단백질을 코딩하는 가공된 mRNA로부터 NMD 엑손의 배제를 억제하고 SCN1A의 발현을 감소시키는 것인 방법.
  58. 제52항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 ASO는 서열 번호 21, 25, 28, 36, 또는 63 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함하는 것인 방법.
  59. 제1항 또는 제2항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로티오에이트 결합 또는 포스포로디아미데이트 결합을 포함하는 백본 변형을 포함하는 것인 방법.
  60. 제1항 또는 제2항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 포스포로디아미데이트 모르폴리노, 잠금 핵산, 펩티드 핵산, 2'-O-메틸, 2'-플루오로, 또는 2'-O-메톡시에틸 모이어티를 포함하는 것인 방법.
  61. 제1항 또는 제2항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 적어도 하나의 변형된 당 모이어티를 포함하는 것인 방법.
  62. 제61항에 있어서, 각각의 당 모이어티는 변형된 당 모이어티인 방법.
  63. 제1항 또는 제2항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 8 내지 50개의 핵염기, 8 내지 40개의 핵염기, 8 내지 35개의 핵염기, 8 내지 30개의 핵염기, 8 내지 25개의 핵염기, 8 내지 20개의 핵염기, 8 내지 15개의 핵염기, 9 내지 50개의 핵염기, 9 내지 40개의 핵염기, 9 내지 35개의 핵염기, 9 내지 30개의 핵염기, 9 내지 25개의 핵염기, 9 내지 20개의 핵염기, 9 내지 15개의 핵염기, 10 내지 50개의 핵염기, 10 내지 40개의 핵염기, 10 내지 35개의 핵염기, 10 내지 30개의 핵염기, 10 내지 25개의 핵염기, 10 내지 20개의 핵염기, 10 내지 15개의 핵염기, 11 내지 50개의 핵염기, 11 내지 40개의 핵염기, 11 내지 35개의 핵염기, 11 내지 30개의 핵염기, 11 내지 25개의 핵염기, 11 내지 20개의 핵염기, 11 내지 15개의 핵염기, 12 내지 50개의 핵염기, 12 내지 40개의 핵염기, 12 내지 35개의 핵염기, 12 내지 30개의 핵염기, 12 내지 25개의 핵염기, 12 내지 20개의 핵염기, 또는 12 내지 15개의 핵염기로 이루어지는 것인 방법.
  64. 제3항에 있어서, 치료제는 안티센스 올리고머(ASO)이며 안티센스 올리고머는 단백질을 코딩하는 NMD 엑손 mRNA의 표적화된 부분에 적어도 80%, 적어도 85%, 적어도 90%, 적어도 95%, 적어도 98%, 적어도 99%, 또는 100% 상보적인 것인 방법.
  65. 제1항에 있어서, SCN1A mRNA 또는 단백질 발현을 평가하는 단계를 추가로 포함하는 방법.
  66. 제2항에 있어서, 대상체는 인간인 방법.
  67. 제2항에 있어서, 대상체는 비인간 동물인 방법.
  68. 제2항에 있어서, 대상체는 태아, 배아, 또는 소아인 방법.
  69. 제1항 또는 제2항에 있어서, 세포는 생체 외 세포인 방법.
  70. 제2항에 있어서, 치료제는 대상체의 수막공간내 주사, 뇌실내 주사, 복강내 주사, 근육내 주사, 피하 주사, 안내, 또는 정맥내 주사에 의해 투여되는 것인 방법.
  71. 제2항에 있어서, 대상체에게 제2 치료제를 투여하는 단계를 추가로 포함하는 방법.
  72. 제71항에 있어서, 제2 치료제는 소분자인 방법.
  73. 제71항에 있어서, 제2 치료제는 ASO인 방법.
  74. 제73항에 있어서, ASO는 서열 번호 115 내지 161 중 어느 하나에 적어도 약 80%, 85%, 90%, 95%, 97%, 또는 100% 상보적인 서열을 포함하는 것인 방법.
  75. 제71항에 있어서, 제2 치료제는 인트론 유지를 교정하는 것인 방법.
  76. 제2항에 있어서, 질환 또는 병태는 알츠하이머병, SCN2A 뇌병증, SCN8A 뇌병증, 또는 SCN5A 부정맥인 방법.
  77. 제30항, 제32항 또는 제34항에 있어서, 질환 또는 병태는 알츠하이머병, SCN2A 뇌병증, SCN8A 뇌병증, 또는 SCN5A 부정맥인 방법.
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