BRPI0417105A - métodos de tratamento de doenças autoimunológicas em pacientes - Google Patents
métodos de tratamento de doenças autoimunológicas em pacientesInfo
- Publication number
- BRPI0417105A BRPI0417105A BRPI0417105-5A BRPI0417105A BRPI0417105A BR PI0417105 A BRPI0417105 A BR PI0417105A BR PI0417105 A BRPI0417105 A BR PI0417105A BR PI0417105 A BRPI0417105 A BR PI0417105A
- Authority
- BR
- Brazil
- Prior art keywords
- patients
- methods
- autoimmune diseases
- treating autoimmune
- diseases
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
"MéTODOS DE TRATAMENTO DE DOENçAS AUTOIMUNOLóGICAS EM PACIENTES". A presente invenção refere-se a terapia de doenças autoimunológicas em que CD20 é detectado em amostra de paciente.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US53136303P | 2003-12-19 | 2003-12-19 | |
| PCT/US2004/040949 WO2005060999A2 (en) | 2003-12-19 | 2004-12-07 | Detection of cd20 in therapy of autoimmune diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BRPI0417105A true BRPI0417105A (pt) | 2007-02-06 |
Family
ID=34710220
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BRPI0417105-5A BRPI0417105A (pt) | 2003-12-19 | 2004-12-07 | métodos de tratamento de doenças autoimunológicas em pacientes |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US20050186206A1 (pt) |
| EP (1) | EP1696955A2 (pt) |
| JP (1) | JP2007514787A (pt) |
| KR (2) | KR20090036154A (pt) |
| CN (1) | CN1917901A (pt) |
| AU (2) | AU2004305560A1 (pt) |
| BR (1) | BRPI0417105A (pt) |
| CA (1) | CA2549122A1 (pt) |
| MX (1) | MXPA06006864A (pt) |
| RU (1) | RU2006126078A (pt) |
| WO (1) | WO2005060999A2 (pt) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000067796A1 (en) | 1999-05-07 | 2000-11-16 | Genentech, Inc. | Treatment of autoimmune diseases with antagonists which bind to b cell surface markers |
| JP2004508420A (ja) * | 2000-09-18 | 2004-03-18 | アイデック ファーマスーティカルズ コーポレイション | B細胞枯渇抗体/免疫調節性抗体の組合せを用いて自己免疫疾患を治療するための併用療法 |
| US9296820B2 (en) | 2003-11-05 | 2016-03-29 | Roche Glycart Ag | Polynucleotides encoding anti-CD20 antigen binding molecules with increased Fc receptor binding affinity and effector function |
| AR053579A1 (es) * | 2005-04-15 | 2007-05-09 | Genentech Inc | Tratamiento de la enfermedad inflamatoria intestinal (eii) |
| MY149159A (en) * | 2005-11-15 | 2013-07-31 | Hoffmann La Roche | Method for treating joint damage |
| EP1806365A1 (en) * | 2006-01-05 | 2007-07-11 | Boehringer Ingelheim International GmbH | Antibody molecules specific for fibroblast activation protein and immunoconjugates containing them |
| AR073295A1 (es) | 2008-09-16 | 2010-10-28 | Genentech Inc | Metodos para tratar la esclerosis multiple progresiva. articulo de fabricacion. |
| WO2010075249A2 (en) | 2008-12-22 | 2010-07-01 | Genentech, Inc. | A method for treating rheumatoid arthritis with b-cell antagonists |
| BRPI1007222A2 (pt) | 2009-01-06 | 2016-02-23 | Inserm Inst Nat De La Santé Et De La Rech Médicale | agente de depleção de células b para tratamento de aterosclerose |
| AR078161A1 (es) | 2009-09-11 | 2011-10-19 | Hoffmann La Roche | Formulaciones farmaceuticas muy concentradas de un anticuerpo anti cd20. uso de la formulacion. metodo de tratamiento. |
| KR20130009760A (ko) | 2010-02-10 | 2013-01-23 | 이뮤노젠 아이엔씨 | Cd20 항체 및 이의 용도 |
| GB201400442D0 (en) * | 2014-01-10 | 2014-02-26 | Sigmoid Pharma Ltd | Compositions for use in the treatment of ulcerative colitis |
| AR104368A1 (es) | 2015-04-03 | 2017-07-19 | Lilly Co Eli | Anticuerpos biespecíficos anti-cd20- / anti-baff |
| TW202337494A (zh) | 2021-11-16 | 2023-10-01 | 美商建南德克公司 | 用莫蘇妥珠單抗治療全身性紅斑狼瘡(sle)之方法及組成物 |
Family Cites Families (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL85035A0 (en) * | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
| US5506126A (en) * | 1988-02-25 | 1996-04-09 | The General Hospital Corporation | Rapid immunoselection cloning method |
| US4861579A (en) * | 1988-03-17 | 1989-08-29 | American Cyanamid Company | Suppression of B-lymphocytes in mammals by administration of anti-B-lymphocyte antibodies |
| US5736137A (en) * | 1992-11-13 | 1998-04-07 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma |
| US7744877B2 (en) * | 1992-11-13 | 2010-06-29 | Biogen Idec Inc. | Expression and use of anti-CD20 Antibodies |
| DK0752248T3 (da) * | 1992-11-13 | 2000-11-13 | Idec Pharma Corp | Terapeutisk anvendelse af kimæriske og radioaktivt mærkede antistoffer mod humant B-lymfocytbegrænset differentieringsantig |
| US5595721A (en) * | 1993-09-16 | 1997-01-21 | Coulter Pharmaceutical, Inc. | Radioimmunotherapy of lymphoma using anti-CD20 |
| US6306393B1 (en) * | 1997-03-24 | 2001-10-23 | Immunomedics, Inc. | Immunotherapy of B-cell malignancies using anti-CD22 antibodies |
| US6171586B1 (en) * | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
| US6368596B1 (en) * | 1997-07-08 | 2002-04-09 | Board Of Regents, The University Of Texas System | Compositions and methods for homoconjugates of antibodies which induce growth arrest or apoptosis of tumor cells |
| US6528624B1 (en) * | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
| US6194551B1 (en) * | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
| US6242195B1 (en) * | 1998-04-02 | 2001-06-05 | Genentech, Inc. | Methods for determining binding of an analyte to a receptor |
| PT1974747E (pt) * | 1998-08-11 | 2012-09-05 | Biogen Idec Inc | Terapias de combinação para linfomas de células b compreendendo a administração de anticorpo anti-cd20 |
| US6224866B1 (en) * | 1998-10-07 | 2001-05-01 | Biocrystal Ltd. | Immunotherapy of B cell involvement in progression of solid, nonlymphoid tumors |
| US6383276B1 (en) * | 1999-03-12 | 2002-05-07 | Fuji Photo Film Co., Ltd. | Azomethine compound and oily magenta ink |
| WO2000067796A1 (en) * | 1999-05-07 | 2000-11-16 | Genentech, Inc. | Treatment of autoimmune diseases with antagonists which bind to b cell surface markers |
| DE60042785D1 (de) * | 1999-06-09 | 2009-10-01 | Immunomedics Inc | Immuntherapie von autoimmunerkrankungen durch die verwendung von b-zell spezifischen antikörpern |
| DE19930748C2 (de) * | 1999-07-02 | 2001-05-17 | Infineon Technologies Ag | Verfahren zur Herstellung von EEPROM- und DRAM-Grabenspeicherzellbereichen auf einem Chip |
| US20020006404A1 (en) * | 1999-11-08 | 2002-01-17 | Idec Pharmaceuticals Corporation | Treatment of cell malignancies using combination of B cell depleting antibody and immune modulating antibody related applications |
| US20030185796A1 (en) * | 2000-03-24 | 2003-10-02 | Chiron Corporation | Methods of therapy for non-hodgkin's lymphoma |
| WO2001074388A1 (en) * | 2000-03-31 | 2001-10-11 | Idec Pharmaceuticals Corporation | Combined use of anti-cytokine antibodies or antagonists and anti-cd20 for the treatment of b cell lymphoma |
| JP2003531588A (ja) * | 2000-04-11 | 2003-10-28 | ジェネンテック・インコーポレーテッド | 多価抗体とその用途 |
| AU2001259142C1 (en) * | 2000-04-25 | 2006-11-23 | Biogen Idec Inc. | Intrathecal administration of rituximab for treatment of central nervous system lymphomas |
| EP1296714B1 (en) * | 2000-06-22 | 2009-08-26 | University Of Iowa Research Foundation | Combination of CpG and antibodies directed against CD19,CD20, CD22 or CD40 for the treatment or prevention of cancer. |
| JP2004508420A (ja) * | 2000-09-18 | 2004-03-18 | アイデック ファーマスーティカルズ コーポレイション | B細胞枯渇抗体/免疫調節性抗体の組合せを用いて自己免疫疾患を治療するための併用療法 |
| US20030103971A1 (en) * | 2001-11-09 | 2003-06-05 | Kandasamy Hariharan | Immunoregulatory antibodies and uses thereof |
| IL157946A0 (en) * | 2001-04-02 | 2004-03-28 | Genentech Inc | Combination therapy |
| US7405047B2 (en) * | 2001-06-25 | 2008-07-29 | Phadia Ab | Method for estimation of the amount of specific cell types |
| JP4424987B2 (ja) * | 2001-09-20 | 2010-03-03 | ボード オブ リージェンツ, ザ ユニバーシティ オブ テキサス システム | Elisaアッセイを用いた循環する治療抗体、抗原および抗原/抗体複合体の測定 |
| CA2463879C (en) * | 2001-10-25 | 2012-12-04 | Genentech, Inc. | Glycoprotein compositions |
| WO2003068821A2 (en) * | 2002-02-14 | 2003-08-21 | Immunomedics, Inc. | Anti-cd20 antibodies and fusion proteins thereof and methods of use |
| US20030219818A1 (en) * | 2002-05-10 | 2003-11-27 | Bohen Sean P. | Methods and compositions for determining neoplastic disease responsiveness to antibody therapy |
-
2004
- 2004-12-07 CN CNA2004800419170A patent/CN1917901A/zh active Pending
- 2004-12-07 CA CA002549122A patent/CA2549122A1/en not_active Abandoned
- 2004-12-07 BR BRPI0417105-5A patent/BRPI0417105A/pt not_active IP Right Cessation
- 2004-12-07 US US11/005,677 patent/US20050186206A1/en not_active Abandoned
- 2004-12-07 JP JP2006545726A patent/JP2007514787A/ja active Pending
- 2004-12-07 EP EP04813284A patent/EP1696955A2/en not_active Withdrawn
- 2004-12-07 MX MXPA06006864A patent/MXPA06006864A/es not_active Application Discontinuation
- 2004-12-07 RU RU2006126078/13A patent/RU2006126078A/ru not_active Application Discontinuation
- 2004-12-07 WO PCT/US2004/040949 patent/WO2005060999A2/en not_active Ceased
- 2004-12-07 KR KR1020097006697A patent/KR20090036154A/ko not_active Withdrawn
- 2004-12-07 AU AU2004305560A patent/AU2004305560A1/en not_active Abandoned
- 2004-12-07 KR KR1020067012188A patent/KR20060109494A/ko not_active Ceased
-
2009
- 2009-05-15 AU AU2009201932A patent/AU2009201932A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005060999A9 (en) | 2008-09-25 |
| CA2549122A1 (en) | 2005-07-07 |
| JP2007514787A (ja) | 2007-06-07 |
| AU2004305560A1 (en) | 2005-07-07 |
| EP1696955A2 (en) | 2006-09-06 |
| WO2005060999A3 (en) | 2006-01-26 |
| WO2005060999A2 (en) | 2005-07-07 |
| CN1917901A (zh) | 2007-02-21 |
| US20050186206A1 (en) | 2005-08-25 |
| AU2009201932A1 (en) | 2009-06-04 |
| MXPA06006864A (es) | 2006-08-23 |
| KR20060109494A (ko) | 2006-10-20 |
| KR20090036154A (ko) | 2009-04-13 |
| RU2006126078A (ru) | 2008-01-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| BRPI0417105A (pt) | métodos de tratamento de doenças autoimunológicas em pacientes | |
| DE60236413D1 (de) | Inhibitoren von hmgb1 zur behandlung von gewebekrankheiten | |
| MY174080A (en) | Use of dpp iv inhibitors | |
| BRPI0408063A (pt) | métodos e composições envolvendo mda-7 | |
| NO20071585L (no) | Ny anvendelse av peptidforbindelser for behandling av benkreftsmerte, kjemoterapi- og nucleosidfremkalt smerte | |
| DE60312309D1 (de) | Verwendung von botulinum toxin zur behandlung von herz- und kreislaufskrankheiten | |
| BRPI0411200A (pt) | método de tratamento de cáncer, métodos de tratamento de paciente humano, artigo industrializado e kit de tratamento de cáncer | |
| DE602004007115D1 (de) | Vorrichtung zur erhaltung des kontaktes zwischen elektrophysiologieelementen und körpergewebe und system dafür | |
| DE60123954D1 (de) | Vorrichtung zum schützen gegen magnetische und elektrische felder | |
| EA202092154A1 (ru) | Комбинированная терапия | |
| CY1105818T1 (el) | Χρησεις του et743 στην θepαπευτικη αγωγη του καρκινου | |
| ATE390928T1 (de) | Zusammensetzungen zur behandlung von hauterkrankungen | |
| WO2022271810A3 (en) | Bicyclic peptidyl pan-ras inhibitors | |
| BRPI0409660A (pt) | método de medida da eficiência de um programa de tratamento de pele | |
| ATE526904T1 (de) | Medizinische geräte mit einem magnetisch aktivierbaren körper oder teil | |
| BRPI0517976A (pt) | métodos de tratamento | |
| DE10390950D2 (de) | Vorrichtung zur Behandlung von Patienten mittels Hirnstimulation | |
| BRPI0417108A (pt) | métodos de tratamento de rejeições de transplantes em pacientes | |
| ATE447426T1 (de) | Elektromagnetische stimulation bei patienten mit osteoporose | |
| BR0311146A (pt) | Uso de tibolona e de modulador de receptor de estrogênio seletivo, e, método e kit para o tratamento de um sintoma relacionado com a deficiência de estrogênio em um paciente do sexo feminino | |
| DE69928521D1 (de) | Cabergolin und pramipexol zur behandlung von krankheiten des zentralnervensystems, insbesondere parkinsonscher krankheit | |
| EA200600989A1 (ru) | Применение габоксадола для лечения бессонницы | |
| ATE449607T1 (de) | Arsentherapie zur behandlung von autoimmunerkrankungen | |
| ITTV20020008A1 (it) | Procedimento per ottenere un manufatto di seta indicato nel trattamento di alcune affezioni cutanee del corpo umano | |
| DE69821970D1 (de) | Verwendung von CITICOLINE ZUR BEHANDLUNG VON MULTIPLER SKLEROSE |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B08F | Application fees: application dismissed [chapter 8.6 patent gazette] |
Free format text: REFERENTE AS 6A E 7A ANUIDADES. |
|
| B08K | Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette] |
Free format text: REFERENTE AO DESPACHO 8.6 PUBLICADO NA RPI 2158 DE 15/05/2012. |