[生物医药论文精品]桂皮酸透皮吸收影响因素的研究

桂皮酸透皮吸收影响因素的研究A1A2A3A0A0A5A5A4A6A7A8A9A10A11A12A13A14A15A16A17A18A19A20A21A18PHA22A18A23A17A18A24A25A26A27A28A29A30A31A9A32A20A33A34A35A36A37A38A39A40A41A8A9A10A31A9A32A20A33A34A42A43A35A44A45A46A47A48A47A48A47A49A50A51A52A53A35FRANZA54A55A56A38A57A58A59A60A61A9A62A63A31A9A64A65A38A51A66A33A21A67A68A69A70A71A72A73A31A9A32A20A74A75A76A77A78A8A9A10A35A79A80A28A31A81A18A31A9A32A20A25A82A18A31A9A30A83A84A59A85A31A9A32A20A86A87A88A89A90A35A74A75A46A78A91A92AZONEA18A93A94A95PGA18A96A10OAA18A97A8A10A98A96A99GLA18A100A95ETHANOL5A101A31A9A32A20A27A102A29A103A104A105A51A26A106A51A35A27A28A33A34A102A107A36A37A46A108A109A49A11A19A20A21A63A110A111A112A100A95A113A114A115A116A117A38A14A15A16A17A63200GA118A119A120A3837A121A117A122A123A23A38PH7A38A24A25A63A124A111A111A125A118A119A126A127A30A8A9A10A35A31A9A32A20A33A34A42A43A38A57A110A112A128A129A130A127A131A132A111A133A134A112A135A128A132A110A111A112A136A120A132A110A111A112A137A136A18A111A133A134A112A135A128A132A110A111A112A136A120A132A110A111A112A137A136A18A110A111A112A136A120A132A110A111A112A137A136A63A138A106A27A102A29A30A32A20A25A82A139A140A141A66A38A142A143A57A110A112A128A129A130A127A131A132A111A133A134A112A135A128A132A110A111A112A136A120A132A110A111A112A137A136A27A28A144A51A42A145A46A108A146A49A147A148A36A37A73A74A75A76A77A78A8A9A10A31A9A32A20A35A74A75A38A63A149A150A142A31A9A151A14A141A152A153A89A36A154A155A46A156A157A158A156A157A49A8A9A10A159A31A9A32A20A159A27A28A29A159HPLCSTUDYONINFLUENCINGFACTORSOFPERCUTANEOUSABSORPTIONOFCINNAMICACIDABSTRACTOBJECTIVESTUDIEDTHEPERCUTANEOUSABSORPTIONEFFECTSOFCINNAMICACIDATDIFFERENTCONCENTRATION,RECEIVINGSOLUTION,PHVALUE,TEMPERATURE,ROTATIONALSPEED,ANDPENETRATIONENHANCERSCREENEDTHEOPTIMUMCONDITIONOFPERCUTANEOUSABSORPTIONMETHODSIMPROVEDFRANZDIFFUSIONCELLWASADOPTEDASTHEAPPARATUSFORINVITRORATSSKINPERMEATIONKINETICPARAMETERSOFPERCUTANEOUSABSORPTION,SUCHASPERMEABILITYAMOUNT,PENETRATIONRATEANDPERCUTANEOUSTIMEDELAY,WEREDETERMINATEDBYHPLCFUTHERMORE,AZONE,PROPYLENEGLYCOL,OLEICACID,GLYCERYLMONOLAURATEANDETHANOLWEREINVESTIGATEDINPERCUTANEOUSABSORPTIONEFFECTSFORSINGLEORCOMBINEDUSERESULTSTHEOPTIMUMCONDITIONIS10ETHANOLINSALINEASRECEIVINGSOLUTION,ADMINISTRATIONCONCENTRATIONIS200GA160A161A162A16337A164A163PHVALUEIS7,ROTATIONALSPEEDIS300R/MINWHEN1AZONE,05OA,10GLAND10PG,05OA,10GLAND10PGAND10GLAND10PGARECHOSEDASCOMPOUNDPENETRATIONENHANCER,PENETRATIONRATEWEREINCREASEDSIGNIFICANTLY,AND,THEFIRSTONEHADTHEBESTEFFECTCONCLUSIONTHERESEARCHWILLPROVIDEEXPERIMENTALDATAFORSKINADMINISTRATIONOFCINNAMICACIDTHROUGHINVESTIGATEDTHESEINFLUENCINGFACTORSKEYWORDSCINNAMICACIDPERCUTANEOUSABSORPTIONPENETRATIONENHANCERHPLC透皮给药TTS又称经皮给药TDS，是指药物以一定的速率通过皮肤，经毛细血管吸收进入循环而产生药效的一类给药方式。具有其它给药方式所不具备的优点它可避免肝脏首过效应，免去人体胃酸和酶对药物的破坏和降解；毒副反应小，出现不良反应时可随时中断治疗；接近于靶器官，药物以恒定的速率进入体内，病人易于接受1。正因为这些优点，透皮给药是目前药物研究的热点之一。桂皮酸CINNAMICACID是中药肉桂的有效成分之一，也可来源于钻山风，枸杞根皮，苏合香，茴香叶等中草药，具有抗炎与抗真G14752G1328G11004，G1000G17836具有G6245G2058G13971G11256细G14002G3698G8554G451G16837G4560G13971G11256细G14002分G2282G451G6245G2058G13971G11256细G14002G1417G16001的G1328G1100423。肉桂有G15929G9791G2173G19463，G5353G9791G5414源，G6967G4518G8502G11183，G8975血通经等G2163效，G3324G457G18341G2306G16213G11065G458中，以肉桂为G1039G16213药物G13464成的方近G989G2325首，是中药G3818G11004治疗G1863G14422炎G1363G11004G20069率G17751G20652的一G2631中药。因G8504，G6117G1216对桂皮酸透皮吸收G2520G5445G2721因G13044进G15904G1114G4466G20576研究，G7100G3324为所有G2559桂皮酸的药物经皮给药G2058G2070G6564G1391G1393G6466。1材料1G171G1214器G4719G8953HPLCG708LC10ATG8905，SPD10AG7828G8991器，G5506G18339进G7691器，N2000G2464通G17959G14406G16901G5049G1328G12461G709；G6925良的G41G85G68G81G93G6205G6967G8756G708G990G9035G19208G1987G12197G6228G17164易有G19492G1856G2508G6564G1391G709；恒G9213G11925G2159G6617G6304器G708G3837G8953G3897G10317G17199G5693G7043G1214器有G19492G1856G2508G709；G83G43G16757G708G2283G1152G17199G3822G2045G7043G1214器G13007G13491有G19492G1856G2508G709；G11017G4388G3837G5191G708G13666国G3897好G7043G12197G6228有G19492G1856G2508G709。1G172药品桂皮酸中国药品生物G2058品G7828定所，批号111302200504，纯度981G173试G2070氮酮；油酸；1，2丙二醇；乙醇；月桂酸甘油酯；G2464蒸水；甲醇G708G14406G16901纯G709；冰醋酸G708G14406G16901纯G709以G990G2282学试G2070均为国产。1G174动物WISTG68G85大鼠22520G购自长春国家生物产业基地G4466G20576动物中心合格证号SCXK吉20030004。2方法与结果2G171离体皮肤G7691品的G2058备与保存大鼠断颈处死后G11004G11017动剃须刀将其背部毛剃干净，立即剪取背部皮肤，将取下的皮肤G5191铺于干净的玻璃板G990，角质层朝下，仔细剥离皮下脂肪层和结缔G13464织，G11004生理盐水反复冲洗干净，置于生理盐水中浸泡，于低G9213冰箱保存备G11004，G4466G20576前自然解冻，并G11004生理盐水浸泡0G175H，于1周内进G15904G4466G20576。每次G4466G20576前目视G7828查皮肤的完整性，不能有任何破损。2G172桂皮酸G14406G16901条件的建立G14406G16901柱G4719G8953CA165A166G7081504G17G25G80G80，5G173G80G709；G8981动G114681冰醋酸水G9354G9094甲醇G70855G2945G709；G7828G8991G8886长2G275G81G80；G8981速0G17G27G80G47G18G80IG81。2G173G7643G1946G7366G13459G13484G2058G12946G4506称取桂皮酸G7643G1946品4G80G，G11004甲醇定G9354于10G80G47G4493G18339G10954中，G18209G2058成G8999度为0G174G80GG18G80G47的桂皮酸G7643G1946品G9354G9094。G1889以G17878G18339的甲醇将其分G2047G12244G18334为G270G45140G45120G45110G4515G4512G175G4511G1725G173GG18G80G47的G7643G1946品G9354G9094。过0G1745G173G80G5506G4392G9400G14192，分G2047进G76911G25G173G47，以G4804G19766G12227对G8999度进G15904G13459性G3250G5414，G8726出桂皮酸G7643G1946G7366G13459方G12255为G60G32510A167XG141102G27G53G320G17G28G28G28G28，G708G81G323G709G15932G7138桂皮酸G33240G1701G7131G172G27G173GG18G80G47G14551G3272内G13459性G1863G13007良好。2G174方G8873学G13783G45312G174G171G12946G4506度G4466G20576G12946G4506吸取桂皮酸G7643G1946品G9354G9094G7080G1704G80GG18G80G47G709，G17842G135055次进G76911G25G173G47，G8991定G4804G19766G12227，G53SG39为0G1735G8，G15932G7138G12946G4506度良好。2G174G172G3250收率G4466G20576取G5062G11705G2559G18339的G7691品G9354G9094G25G1233，分G2047G2164入桂皮酸G7643G1946品G9354G9094G7080G1704G80GG18G80G47G7090G175，0G175，1G170，1G170，1G175，1G175G80G47，G3324G990G17860G14406G16901条件下G8991定桂皮酸的G2559G18339，G16757G12651其G5191均G3250收率为G28G28G1753G8，G53SG39为1G170G26G8G708G81G32G25G709。2G174G173G12295定性G4466G20576将桂皮酸G7643G1946品G18209G2058成G8999度为0G1704G80GG18G80G47的水G9354G9094，置于3G26G263的水G9032中G2164热，分G2047于2，4，G25，G27，10，12，24H取G7691，G8991定桂皮酸G2559G18339，以G4804G19766G12227G16757G12651G53SG39为0G17G273G8，结G7536G15932G7138G1391试品G9354G9094G332424H内G12295定。2G175桂皮酸透皮吸收G4466G20576取出G1931G15267备G11004大鼠背部皮肤，自然解冻，将皮肤G3278定于G6925良G41G85G68G81G93G6205G6967G8756G990G1391给G4472和接收G8756G11464G5464为2G70G80，G19766G12227为3G1714G70G80A168，G1363角质层G19766G2533G990，G11004G5389G12795G3853G3278定，G3324G1391给G8756中G2164入2G80G47G9195透G1431进G2070G9354G9094，接收G8756中G2164入G26G80G47生理盐水G1328为接收G9094，G3853层以37G263水G9032恒G9213，G11925G2159G6617G6304G4388以100G85G18G80IG81的速度G6617G6304，分G2047于2，4，G25，G27，10，12，24H取出接收G4472中1G80G47接收G9094，立即G15929G2164等G18339的G20056G921337G263的G7044G21104接收G9094。取出的接收G9094过0G1745G173G80G5506G4392G9400G14192，G11004G20652效G9094G11468G14406G16901G8873G8991定桂皮酸G2559G18339。并G6365下G2027G1856式G16757G12651G13059G12227G9195透G18339G708G52G709。式中，CG81G12544G81G1022取G7691点G8991G5483的药物G8999度G173GG18G80G47；CIG12544IG1022取G7691点G8991G5483的药物G8999度G173GG18G80G47；G36G9195透G19766G12227G70G80A168；以G13059G12227G9195透G18339G52对时G19400T进G15904G13459性G3250G5414所G5483方G12255即为G43IGG88G70HI方G12255，根G6466G11464G13459方G12255可以G8726出G12295G5589G8981G18339G708G51G709和G9394后时G19400G708G55A169A170A171G709，G9195透G13007G6980G708G51G80G709等于药物的G12295G5589G8981G18339G19512以G1391药G8756中药物G9354G9094的G8999度；G3698G9195G8616G40G41的G16757G12651以对G10043G13464桂皮酸的G12295G5589G8981G18339为G2454G8616而G5483。2G175G171接收G9094对桂皮酸透皮吸收的G5445G2721400G/ML桂皮酸水G9354G9094为G1391给G9094，37G263水G9032恒G9213，100G85G18G80IG81的速度G6617G6304条件下，G13783G4531以生理盐水G45110G45120G708V/VG709乙醇生理盐水为接收G9094时桂皮酸透皮吸收G5785G1929，G16764G16782接收G9094对桂皮酸透皮吸收的G5445G2721。透皮速率G5132G6980和G43IGG88G70HI方G12255G16277G159321。表1不同接收液时桂皮酸透皮速率常数和HIGUCHI方程（XS，N5）A172A173A174HIGUCHIA175A176RG51G18G/CMA177A178A179A180A181A182A183A184A185A186A179A187A188A189A190A191A192A193A194A193A195A195A196A197A198A193A194A199A200A201A196A193A194A201A202A202A203A193A194A193A195A195A196A193A194A193A200A204A201A202A194A204A193A199A194A196A203A200A193A205A206A207A208A187A188A191A192A193A194A200A200A193A200A197A198A193A194A193A204A204A201A193A194A201A209A200A202A193A194A200A200A193A200A193A194A193A200A203A201A193A194A204A200A193A194A209A202A203A193A205A206A207A208A187A188A191A192A193A194A193A204A202A201A197A198A193A194A200A199A199A193A193A194A201A195A209A196A193A194A193A204A202A201A193A194A193A200A193A203A200A194A196A209A203A194A203A196结G7536G15932G7138接收G9094对桂皮酸透皮吸收的G5445G2721G17751大G83G310G1705，G13520合G12295G5589G8981G18339G51和G9394后时G19400G708G55A210A211A212G709G1016G1022G2454G6980G8616G17751，以10G8乙醇生理盐水为接收G9094时，桂皮酸透皮吸收效G7536G7380G1351。2G175G172G8999度对桂皮酸透皮吸收的G5445G272110G8乙醇生理盐水为接收G9094，37G263水G9032恒G9213，100G85G18G80IG81的速度G6617G6304条件下，G13783G4531给药G8999度分G2047为200G451300G451400G/ML时桂皮酸透皮吸收G5785G1929，G16764G16782给药G8999度对桂皮酸透皮吸收的G5445G2721。透皮速率G5132G6980和G43IGG88G70HI方G12255G16277G159322。表2不同药物浓度的桂皮酸透皮速率常数和HIGUCHI方程（XS，N5）A213A214A215A216A217G/MLHIGUCHIA218A219RA220A221G/CMA222A223A224A225A226A227A228A229A230A221A224A220A231/CMA222A223A224A225A232A233A233A234A235A233A236A233A237A237A232A238A239A233A236A233A240A241A240A233A236A242A243A237A242A233A236A233A237A237A232A233A236A233A233A244A232A233A236A243A242A233A236A240A233A232A236A245A243A246A244A233A247A248A240A233A233A234A235A233A236A233A241A244A240A238A239A233A236A233A245A232A242A233A236A242A242A241A233A233A236A233A241A244A240A233A236A233A233A232A240A233A236A242A233A233A236A243A241A232A236A245A244A246A244A233A247A248A249A233A233A234A235A233A236A244A244A233A244A238A239A233A236A233A241A241A242A233A236A242A245A244A249A233A236A244A244A233A244A233A236A233A244A232A242A233A236A241A244A233A236A245A249A232A236A245A237A246A244A233A247A248结G7536G15932G7138桂皮酸透皮吸收的G12295G5589G8981G18339G51随G11540给药G8999度的G3698G2164而G2331G20652，G11013于给药G8999度不G2528，G6117G1216应G16825G1186G9195透G13007G6980G51G80和G9394后时G19400G708G55A250A251A252G709G1016G1022G2454G6980进G15904G8616G17751，给药G8999度对桂皮酸透皮吸收G8821有G5445G2721G83G330G1705，因G8504G17885G6333给药G8999度为低G2070G18339200G/ML。2G175G173G9213度对桂皮酸透皮吸收的G5445G272110G8乙醇生理盐水为接收G9094，200G/ML桂皮酸水G9354G9094为G1391给G9094，100G85G18G80IG81的速度G6617G6304条件下，G13783G45313G26G263G45134G263G45132G263水G9032恒G9213时桂皮酸透皮吸收G5785G1929，G16764G16782G9213度对桂皮酸透皮吸收的G5445G2721。透皮速率G5132G6980和G43IGG88G70HI方G12255G16277G159323。表3不同温度时桂皮酸透皮速率常数和HIGUCHI方程（XS，N5）A253A254A255A111A150HIGUCHIA146A0RG51G18G/CMA1A148A149A150A2A152A3A4A5A6A149A7A8A156A9A101A10A101A11A11A12A159A13A101A10A101A14A15A14A101A10A16A158A11A16A101A10A101A11A11A12A101A10A101A101A17A12A101A10A158A16A101A10A14A101A7A18A156A9A101A10A101A19A15A158A159A103A101A10A101A14A16A20A101A10A16A16A19A158A101A10A101A19A15A158A101A10A101A101A17A20A101A10A15A12A101A10A20A16A7A21A156A9A101A10A101A19A14A158A159A103A101A10A101A14A15A20A101A10A16A16A11A19A101A10A101A19A14A158A101A10A101A101A12A17A101A10A15A16A101A10A15A20结G7536G15932G7138G9213度对桂皮酸透皮吸收的G5445G2721G17751大G83G310G1705，G12295G5589G8981G18339G51随G11540G9213度的G2331G20652而G2331G20652，3G26G263时桂皮酸透皮吸收效G7536G7380G1351。2G175G174G83G43G1552对桂皮酸透皮吸收的G5445G2721接收G9094为10G8乙醇生理盐水，给药G8999度为200G/ML，37G263水G9032恒G9213G17728速为100G85G18G80IG81条件下，以PH4A105G4517A102的G11979酸盐G13543冲G9094和蒸G20323水G83G43G32G26为G9354G2070G18209G2058G1391给G9094，G13783G4531不G2528G83G43G1552时桂皮酸透皮吸收G5785G1929。透皮速率G5132G6980和G43IGG88G70HI方G12255G16277G159324。表4不同PH值时桂皮酸透皮速率常数和HIGUCHI方程（XS，N5）G83G43G1552HIGUCHIA22A23RG51/G/CMA24A25A26A27A28A29A30A31A32A33A34A35A123A36A37A38A39A123A39A40A41A42A43A44A39A123A39A45A46A47A39A123A42A160A42A160A39A123A39A40A41A42A39A123A39A39A46A48A46A123A46A45A39A123A45A46A35A37A38A39A123A39A47A47A40A43A49A39A123A39A45A160A45A39A123A42A48A47A42A39A123A39A47A47A40A39A123A39A39A46A40A39A123A48A42A39A123A45A39A50A123A51A37A38A39A123A39A47A39A52A43A49A39A123A39A45A52A48A39A123A160A42A45A160A39A123A39A47A39A52A39A123A39A39A46A47A39A123A48A42A39A123A45A45结G7536G15932G7138PH对桂皮酸透皮吸收的G5445G2721G17751大G83G310G1705，桂皮酸G3324离G4388时PH7G172不易透过皮肤，G3324分G4388时PH7G4514G175易于透过皮肤，PH为7时桂皮酸透皮吸收效G7536G7380G1351。2G175G175G17728速对桂皮酸透皮吸收的G5445G272110G8乙醇生理盐水为接收G9094，200G/ML桂皮酸水G9354G9094为G1391给G9094，37G263水G9032恒G9213条件下，G13783G4531G17728速分G2047为100G85G18G80IG81G451300G85G18G80IG81G451500G85G18G80IG81时桂皮酸的透皮吸收G5785G1929。透皮速率G5132G6980和G43IGG88G70HI方G12255G16277G159325。表4不同转速时桂皮酸透皮速率常数和HIGUCHI方程（XS，N5）A53A54A166A55A56A57A58A59A60HIGUCHIA61A62RG51G18G/CMA63A64A65A60A66A67A68A69A70A56A65A100A71A71A72A73A71A74A71A75A75A76A77A78A71A74A71A79A80A79A81A82A83A84A85A83A81A82A81A85A85A86A81A82A81A81A87A86A81A82A84A83A81A82A88A81A88A81A81A89A90A81A82A81A85A85A91A92A93A81A82A81A88A86A86A81A82A83A163A86A85A81A82A81A85A85A91A81A82A81A81A87A87A81A82A85A163A81A82A88A81A85A81A81A89A90A81A82A81A85A85A88A92A93A81A82A81A85A163A84A81A82A83A94A85A83A81A82A81A85A85A88A81A82A81A81A87A163A87A82A81A84A81A82A88A87结G7536G15932G7138G17728速对桂皮酸透皮吸收的G5445G2721G17751小，G12295G5589G8981G18339G51变G2282不大G83G330G1705，G9394后时G19400G708G55A95A96A97G709变G2282G17751大G83G310G1705，G17728速为300G85G18G80IG81时G9394后时G19400G7380短。2G175G17G25G1431G9195G2070对桂皮酸透皮吸收的G5445G27212G175G17G25G171单一G1431G9195G2070对桂皮酸透皮吸收的G5445G2721接收G9094为10G8乙醇生理盐水，给药G8999度为200G/ML，37G263水G9032恒G9213，PH7，G17728速为300G85G18G80IG81条件下，G13783G4531以下单一G1431G9195G2070对桂皮酸透皮吸收G5785G1929的G5445G272110G8G45120G8G45130G8乙醇ETHANOL；5G8G45110G8G45120G8G45130G8丙二醇G51G；0G175G8G4511G8G4513G8G4515G8氮酮G36G93OG81E；0G175G8G4511G8G4513G8G4515G8G451G26G8G451G28G8油酸OG36；5G8G45110G8G45115G8G45120G8月桂酸甘油酯GG47。透皮速率G5132G6980和G43IGG88G70HI方G12255G16277G15932G25。表6单一促渗剂时桂皮酸透皮速率常数和HIGUCHI方程（XS，N5）A98A99A102HIGUCHIA104A105RG51/G/CMA106A107A108A109A110A112A113A114A115A116A108A167A117A169A118A119A120A121A118A113A122A124A125A126A125A127A127A128A129A130A125A126A125A131A132A132A125A126A133A134A132A127A125A126A125A127A127A128A125A126A125A125A135A135A125A126A127A134A125A126A131A125A135A135A125A136ETHANOLA137A138A125A126A125A128A127A128A129A130A125A126A125A139A139A125A125A126A133A139A140A140A125A126A125A128A127A128A125A126A125A125A135A139A141A135A126A128A127A125A126A139A132A125A126A134A132A132A125A136ETHANOLA137A138A125A126A125A127A132A135A129A130A125A126A125A127A139A139A125A126A133A140A132A139A125A126A125A127A132A135A125A126A125A125A132A135A141A135A126A135A125A125A126A131A131A125A126A133A128A131A125A136ETHANOLA137A138A125A126A125A128A135A140A129A130A125A126A125A128A139A127A125A126A133A128A133A132A125A126A125A128A135A140A125A126A125A125A135A140A141A135A126A135A132A125A126A128A131A125A126A140A127A127A136A142A143A137A138A125A126A125A127A131A127A129A130A125A126A125A140A131A132A125A126A133A128A135A132A125A126A125A127A131A127A125A126A125A125A131A132A141A135A126A131A140A125A126A140A133A125A126A133A140A135A125A136A142A143A137A138A125A126A125A127A128A134A129A130A125A126A125A127A134A135A125A126A133A134A128A133A125A126A125A127A128A134A125A126A125A125A139A128A141A135A126A125A139A125A126A131A132A125A126A133A133A132A125A136A142A143A137A138A125A126A125A128A140A135A129A130A125A126A125A133A139A128A125A126A133A140A139A140A125A126A125A128A140A135A125A126A125A125A140A134A141A132A126A125A127A135A126A125A127A125A126A134A127A131A125A136A142A143A137A138A125A126A125A128A128A135A129A130A125A126A125A131A125A132A125A126A133A133A135A128A125A126A125A128A128A135A125A126A125A125A133A127A141A125A126A139A134A125A126A127A128A125A126A134A125A125A126A127A136A144A145A147A151A153A137A138A125A126A125A134A133A131A129A130A125A126A125A128A139A140A125A126A133A134A140A139A125A126A125A134A133A131A125A126A125A125A134A140A141A141A125A126A127A132A125A126A128A134A135A126A139A135A135A136A144A145A147A151A153A137A138A125A126A125A133A134A127A129A154A125A126A125A133A139A132A125A126A133A133A135A128A125A126A125A133A134A127A125A126A125A125A127A131A141A141A125A126A133A134A125A126A131A140A135A126A140A134A131A136A144A145A147A151A153A137A138A125A126A125A139A127A140A129A154A125A126A135A133A127A131A125A126A133A134A131A127A125A126A125A139A127A140A125A126A125A125A127A127A141A132A126A133A140A135A126A133A139A135A126A135A133A127A136A144A145A147A151A153A137A138A125A126A125A131A127A139A129A154A125A126A125A128A139A127A125A126A133A133A128A127A125A126A125A131A127A139A125A126A125A125A139A125A141A135A126A131A135A135A126A131A139A125A126A140A140A125A126A127A136A155A144A137A138A125A126A125A134A140A125A129A130A125A126A125A139A140A134A125A126A133A125A132A127A125A126A125A134A140A125A125A126A125A125A127A140A141A141A125A126A140A134A125A126A128A135A135A126A127A140A135A136A155A144A137A138A125A126A125A127A131A134A129A130A125A126A135A135A135A127A125A126A133A132A133A131A125A126A125A127A131A134A125A126A125A125A128A135A141A132A126A125A140A125A126A140A140A125A126A133A140A131A136A155A144A137A138A125A126A125A131A127A131A129A130A125A126A125A127A135A127A125A126A133A139A125A135A125A126A125A131A127A131A125A126A125A125A135A128A141A135A126A128A139A125A126A139A134A125A126A139A128A127A136A155A144A137A138A125A126A125A127A135A128A129A130A125A126A125A131A133A134A125A126A133A139A133A127A125A126A125A127A135A128A125A126A125A125A131A134A141A125A126A140A140A125A126A127A133A125A126A133A131A140A136A155A144A137A138A125A126A125A139A131A125A129A130A125A126A125A135A139A140A125A126A133A134A125A140A125A126A125A139A131A125A125A126A125A125A127A131A141A125A126A132A140A125A126A131A135A135A126A135A128A133A136A155A144A137A138A125A126A125A140A135A139A129A130A125A126A125A132A125A140A125A126A133A134A132A128A125A126A125A140A135A139A125A126A125A125A139A139A141A125A126A132A133A125A126A131A131A135A126A132A133A127A136A143A157A137A138A125A126A125A140A131A135A129A130A125A126A128A128A132A131A125A126A134A128A139A134A125A126A125A140A131A135A125A126A125A125A128A134A141A139A126A125A127A128A126A131A134A135A126A131A132A135A125A136A143A157A137A138A125A126A132A128A134A140A129A130A125A126A135A135A131A127A125A126A133A135A132A134A125A126A132A128A134A140A125A126A125A135A135A132A141A141A125A126A128A139A125A126A131A139A128A126A128A133A135A127A136A143A157A137A138A125A126A125A139A133A127A129A130A125A126A131A125A134A134A125A126A134A131A134A132A125A126A125A139A133A127A125A126A125A125A131A127A141A128A126A128A128A131A126A127A135A135A126A132A139A132A125A136A143A157A137A138A125A126A125A127A132A128A129A130A125A126A125A131A140A132A125A126A133A127A133A128A125A126A125A127A132A128A125A126A125A125A131A132A141A125A126A140A135A125A12