TR200401803T2 - NOS önleyicileri için yeni farmasötik kullanımlar. - Google Patents

NOS önleyicileri için yeni farmasötik kullanımlar.

Info

Publication number
TR200401803T2
TR200401803T2 TR2004/01803T TR200401803T TR200401803T2 TR 200401803 T2 TR200401803 T2 TR 200401803T2 TR 2004/01803 T TR2004/01803 T TR 2004/01803T TR 200401803 T TR200401803 T TR 200401803T TR 200401803 T2 TR200401803 T2 TR 200401803T2
Authority
TR
Turkey
Prior art keywords
nos
inhibitors
alone
combination
pharmaceutical uses
Prior art date
Application number
TR2004/01803T
Other languages
English (en)
Inventor
Adams Iii Lowe John
Nowakowski Jolanta
Alfred Volkmann Robert
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of TR200401803T2 publication Critical patent/TR200401803T2/tr

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/468-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/472Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/06Antimigraine agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Psychiatry (AREA)
  • Immunology (AREA)
  • Anesthesiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

Mevcut bulus, nitrik oksit sintaz (NOS) önleyicileri olarak aktivite gösteren bilesiklerin yeni farmastik kullanimlari ile ilgilidir. Spesifik olarak bu, NOS önleyicilerinin, özellikle de seçici nöronal NOS (N-NOS) önleyicilerinin: (a) psöryazinin tedavisinde tek basina veya baska bir aktif madde ile kombinasyon halinde;(b) iltihabik bozukluklarin tedavisinde narkotik bir analjezik (örn.,morfin veya demerol gibi opiatlar) ile kombinasyon halinde; (d) tek basina veya alginin gelistirilmesi için diger aktif maddelerle kombinasyon halinde; ve (e) tek basina veya apenea, narkolepsi ve insomnia gibi uyku bozukluklarinin tedavisinde diger aktif maddelerle kombinasyon halinde kullanilmasi ile ilgilidir.
TR2004/01803T 1998-08-11 1999-08-05 NOS önleyicileri için yeni farmasötik kullanımlar. TR200401803T2 (tr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US9615298P 1998-08-11 1998-08-11

Publications (1)

Publication Number Publication Date
TR200401803T2 true TR200401803T2 (tr) 2004-11-22

Family

ID=22255853

Family Applications (3)

Application Number Title Priority Date Filing Date
TR2004/01803T TR200401803T2 (tr) 1998-08-11 1999-08-05 NOS önleyicileri için yeni farmasötik kullanımlar.
TR2001/03661T TR200103661T2 (tr) 1998-08-11 1999-08-05 NOS önleyicileri için yeni farmasötik kullanımlar.
TR2001/00434T TR200100434T2 (tr) 1998-08-11 1999-08-05 Nos önleyicileri için yeni farmasötik kullanımlar

Family Applications After (2)

Application Number Title Priority Date Filing Date
TR2001/03661T TR200103661T2 (tr) 1998-08-11 1999-08-05 NOS önleyicileri için yeni farmasötik kullanımlar.
TR2001/00434T TR200100434T2 (tr) 1998-08-11 1999-08-05 Nos önleyicileri için yeni farmasötik kullanımlar

Country Status (37)

Country Link
US (1) US20020151572A1 (tr)
EP (1) EP1109556A2 (tr)
JP (1) JP2002522498A (tr)
KR (1) KR20010085364A (tr)
CN (1) CN1323211A (tr)
AP (1) AP2001002067A0 (tr)
AR (1) AR020009A1 (tr)
AU (1) AU749439B2 (tr)
BR (1) BR9912906A (tr)
CA (1) CA2340200A1 (tr)
CO (1) CO5130011A1 (tr)
CR (1) CR6302A (tr)
CZ (1) CZ2001486A3 (tr)
DZ (1) DZ2867A1 (tr)
EA (1) EA200100125A1 (tr)
EE (1) EE200100084A (tr)
GE (1) GEP20043252B (tr)
GT (1) GT199900127A (tr)
HK (1) HK1041819A1 (tr)
HR (1) HRP20010099A2 (tr)
HU (1) HUP0103113A3 (tr)
ID (1) ID28227A (tr)
IL (1) IL141031A0 (tr)
IS (1) IS5814A (tr)
MA (1) MA26670A1 (tr)
NO (1) NO20010685L (tr)
NZ (1) NZ509298A (tr)
OA (1) OA11595A (tr)
PA (1) PA8479801A1 (tr)
PE (1) PE20001025A1 (tr)
PL (1) PL346842A1 (tr)
SK (1) SK1702001A3 (tr)
SV (1) SV1999000121A (tr)
TN (1) TNSN99154A1 (tr)
TR (3) TR200401803T2 (tr)
WO (1) WO2000009130A2 (tr)
YU (1) YU9601A (tr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010049379A1 (en) 1997-08-27 2001-12-06 Lowe John Adams 2-aminopyridines containing fused ring substituents
EP1267862A2 (en) 2000-02-22 2003-01-02 Cellegy Canada Inc. Methods and compositions for improving sleep
CN100430399C (zh) * 2002-03-20 2008-11-05 昆士兰大学 包含一氧化氮供体和阿片样物质止痛剂的组合物和方法
WO2005007627A1 (ja) * 2003-07-18 2005-01-27 Nihon Nohyaku Co., Ltd. フェニルピリジン誘導体、その中間体及びこれを有効成分とする除草剤
US9120750B2 (en) 2013-03-07 2015-09-01 Northwestern University 2-Aminopyridine-based selective neuronal nitric oxide synthase inhibitors
US10759791B2 (en) 2014-11-04 2020-09-01 Northwestern University Mammalian and bacterial nitric oxide synthase inhibitors
WO2016073623A2 (en) 2014-11-04 2016-05-12 Northwestern University Mammalian and bacterial nitric oxide synthase inhibitors

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CZ291647B6 (cs) * 1996-03-29 2003-04-16 Pfizer Inc. 6-Fenylpyridyl-2-aminové deriváty, jejich použití a farmaceutické kompozice na jejich bázi
HN1997000027A (es) * 1996-12-06 1997-06-05 Pfizer Prod Inc Derivados de 6-fenil piridil - 2 amina
YU35699A (sh) * 1997-02-10 2002-06-19 Pfizer Products Inc. 2-amino-6-(2-supstituisan-4-fenoksi)-supstituisani piridini
HN1998000118A (es) * 1997-08-27 1999-02-09 Pfizer Prod Inc 2 - aminopiridinas que contienen sustituyentes de anillos condensados.
HN1998000125A (es) * 1997-08-28 1999-02-09 Pfizer Prod Inc 2-aminopiridinas con sustituyentes alcoxi ramificados
SE9703693D0 (sv) * 1997-10-10 1997-10-10 Astra Pharma Prod Novel combination

Also Published As

Publication number Publication date
US20020151572A1 (en) 2002-10-17
HUP0103113A2 (hu) 2002-01-28
NO20010685D0 (no) 2001-02-09
TNSN99154A1 (fr) 2005-11-10
WO2000009130A3 (en) 2000-05-18
GT199900127A (es) 2001-01-30
KR20010085364A (ko) 2001-09-07
ID28227A (id) 2001-05-10
WO2000009130A2 (en) 2000-02-24
HUP0103113A3 (en) 2002-02-28
EP1109556A2 (en) 2001-06-27
NO20010685L (no) 2001-04-09
CN1323211A (zh) 2001-11-21
HK1041819A1 (zh) 2002-07-26
AR020009A1 (es) 2002-03-27
GEP20043252B (en) 2004-06-25
IL141031A0 (en) 2002-02-10
EE200100084A (xx) 2002-08-15
OA11595A (en) 2004-08-19
EA200100125A1 (ru) 2001-08-27
HRP20010099A2 (en) 2002-02-28
NZ509298A (en) 2005-02-25
AU749439B2 (en) 2002-06-27
AP2001002067A0 (en) 2001-03-31
PE20001025A1 (es) 2000-10-11
CZ2001486A3 (cs) 2002-06-12
YU9601A (sh) 2003-12-31
CO5130011A1 (es) 2002-02-27
TR200100434T2 (tr) 2001-07-23
DZ2867A1 (fr) 2003-12-15
SV1999000121A (es) 2000-07-06
CA2340200A1 (en) 2000-02-24
PA8479801A1 (es) 2000-09-29
TR200103661T2 (tr) 2002-06-21
SK1702001A3 (en) 2003-02-04
MA26670A1 (fr) 2004-12-20
AU4924899A (en) 2000-03-06
JP2002522498A (ja) 2002-07-23
PL346842A1 (en) 2002-02-25
BR9912906A (pt) 2001-05-08
CR6302A (es) 2004-03-24
IS5814A (is) 2001-01-16

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