-血壓控制與腦出血治療和預(yù)防課件

血壓控制與腦出血治療和預(yù)防北京大學(xué)第一醫(yī)院神經(jīng)科黃一寧教授ynhuang@血壓控制與腦出血治療和預(yù)防北京大學(xué)第一醫(yī)院神經(jīng)科1PrimaryIntracerebralHaemorrhage10-15%allstrokes(Caucasians)20-30%inAsian/AfricanPathology(80-90%ofallICH)HypertensiveangiopathyAmyloidangiopathySitesBasalGangliaPutamen(40%),thalamus(15%),caudate(5-10%)Cerebellum(10%),pons(10%)Lobar(10-20%)PrimaryIntracerebralHaemorrh2HaematomaevolutionHaematomaevolution3EarlyhaematomaexpansionOnset-CTinterval(h)ProspectiveRetrospectiveBrottFujiiKazuiTakizawa0-338%18%36%17%3-6N/A8%16%6%6-24N/A2%10%0%EarlyhaematomaexpansionProsp4Peri-haematomaloedemainICHPreciseaetiologyunclearcytotoxicvsvasogenicIsthereaperi-haematomal‘ischaemicpenumbra?’RationalacuteBPloweringrequiresbetterunderstandingofperi-haematomaloedemaPeri-haematomaloedemainICHP5Surgicaltreatment

STICHtrialresultsSurgicaltreatment

STICHtrial6Medicaltreatment

rFVII(NovoSeven?)Mayeretal.NEJM2005;352:777-85Medicaltreatment

rFVII(NovoS7ReductionofhaematomaexpansionMayeretal.NEJM2005;352:777-85Reductionofhaematomaexpansi8北大醫(yī)院臨床診治方案北大醫(yī)院臨床診治方案9平掃CT應(yīng)該作為首選，對(duì)腦出血和蛛網(wǎng)膜下腔出血均很敏感。核磁對(duì)可疑的腦出血診斷和處理上也很有幫助。腦出血包括硬膜外和硬膜下出血、蛛網(wǎng)膜下腔出血、腦室出血、梗塞后出血以及腦實(shí)質(zhì)出血。一定要考慮到：凝血疾病、外傷、血管損傷、靜脈血栓形成，以及動(dòng)脈瘤破裂。平掃CT應(yīng)該作為首選，對(duì)腦出血和蛛網(wǎng)膜下腔出血均很敏感。10下述步驟應(yīng)該是同步進(jìn)行

評(píng)估生命體癥：判斷患者做影像學(xué)檢查時(shí)是否能忍受，是否要插管。若認(rèn)為需要插管，可以使用超短作用的神經(jīng)肌肉阻斷劑或者鎮(zhèn)靜劑，避免長(zhǎng)時(shí)間影響觀察患者運(yùn)動(dòng)功能和神經(jīng)功能。對(duì)于血壓嚴(yán)重升高的患者應(yīng)該評(píng)估是否有心肌的損傷。下述步驟應(yīng)該是同步進(jìn)行

評(píng)估生命體癥：判斷患者做影像學(xué)檢查時(shí)11血液檢查：PT、INR、PTT、血小板計(jì)數(shù)和全血計(jì)數(shù)、D－Dimer、纖維蛋白原、電解質(zhì)、BUN、Cr、血糖、肝功能、血型。需要與神經(jīng)外科聯(lián)系：小腦出血時(shí)神經(jīng)外科急癥；非優(yōu)勢(shì)半球的腦葉出血，臨床神經(jīng)功能進(jìn)行性加重；對(duì)于特殊患者，如年輕患者、優(yōu)勢(shì)半球不清楚，等情況下，考慮需要減壓術(shù)者。血液檢查：PT、INR、PTT、血小板計(jì)數(shù)和全血計(jì)數(shù)、D－D12根據(jù)指南控制血壓。所有需要連續(xù)靜脈降壓的患者，都應(yīng)該急診放置動(dòng)脈導(dǎo)管，監(jiān)測(cè)血壓和中心靜脈壓，同時(shí)使用靜脈降壓藥。一旦決定藥?kù)o脈降壓治療，必須指定專人床旁監(jiān)測(cè)血壓和治療效果，直至血壓得到控制。根據(jù)指南控制血壓。所有需要連續(xù)靜脈降壓的患者，都應(yīng)該急診放置13Roleofbloodpressureobservationalstudies-mortalityadmissionBPandmortalitySBP(mmHg)1monthmortality(%)FogelholmVemmosRoleofbloodpressureadmissio14OnsetofICH3-66-12hours12hrstooneweek1-4weeksmonthsBPloweringhaemorrhagerebleedingoedemastrokerecurrenceBPlowering

PotentialtherapeuticmechanismsOnsetofICH3-66-1212hrst15腦出血患者血壓控制方案

拉貝洛爾labetalol5－100mg/h，間斷注入，每次10－40mg，或者 連續(xù)點(diǎn)滴2－8mg/min我國(guó)藥典禁忌在腦出血使用拉貝咯爾

艾司洛爾esmolol負(fù)荷量500mcg/kg；維持量50－200mcg.kg-1min硝普鈉nitroprusside 0.5-10mcg.kg-1min-1尼卡地平nicardipine 5mg/h,每15分鐘增加2.5mg/h,最大量為15mg/h肼苯噠嗪hydralazine 10-20mg,q4-6h依那普利0.625-1.2mgq6h,根據(jù)需要調(diào)節(jié)劑量

腦出血患者血壓控制方案

16GuidelinesforAcuteBPManagementStartmedicationTargetICHAHA(1999)≥180/105mmHg<180/105mmHgISH(2003)≥180/105mmHg<180/105mmHgNZ(2003)MeanBP≥130mmHgMeanBP<130mmHgAnystrokeAust(2003)≥200/110mmHgUpto20%reductionEUSI(2003)>220/120mmHg180/100-105mmHg(HT)160-180/90-105mmHg(non-HT)UK(2004)ifcomplicationsareapparentNotdescribedGuidelinesforAcuteBPManage17對(duì)于腦出血早期幾個(gè)小時(shí)內(nèi)可以根據(jù)下述步驟：收縮壓>230mmHg，或者舒張壓>140mmHg，間隔5分鐘測(cè)量2次血壓，開始使用硝普鈉收縮壓180－230mmHg，舒張壓105－140mmHg，或者平均動(dòng)脈壓≥130mmHg，間隔20分鐘測(cè)量2次，開始靜脈使用拉貝洛爾、艾司洛爾、依那普利，避免口服或舌下含服硝苯地平。收縮壓<180mmHg舒張壓<105mmHg，暫緩使用抗高血壓藥，除非懷疑出現(xiàn)了冠狀動(dòng)脈缺血性疾病。選擇用藥應(yīng)該根據(jù)患者實(shí)際情況和禁忌癥，如拉貝洛爾不藥用于哮喘的患者。如果有顱內(nèi)壓監(jiān)測(cè)，應(yīng)該保持腦灌注壓>70mmHg。當(dāng)懷疑由于降低血壓引起臨床癥狀惡化，應(yīng)考慮調(diào)整血壓。對(duì)于腦出血早期幾個(gè)小時(shí)內(nèi)可以根據(jù)下述步驟：收縮壓>230m18問題什么時(shí)候降血壓降到多少合適降壓速度問題什么時(shí)候降血壓19INTERACTpilotphase

(LancetNeurology2008;7:391-399.)INTERACTpilotphase

(LancetN20PathophysiologyElevatedBloodPressureOngoingbleedingRe-bleedingHaematomasizePooroutcomeCerebraloedemaPathophysiologyElevatedBlood21VanguardPhase

ProtocolSchemaRandomisationAcuteICH-onsetwithin6hoursSBP≥150and≤220mmHgRepeatCTscans24+72hrsVitalsignsandBPover7days28dayand3monthfollow-upIntensive

BPloweringTargetSBP<140mmHgGuideline-basedBPmanagementTargetSBP<180mmHgVanguardPhase

ProtocolSchem22SystolicbloodpressuredifferencesSystolicbloodpressurediffer23Crudemean(SD)changeinhematomavolumebygroupVolume(ml)GuidelinegroupIntensivegroupBaseline24hours12.715.414.215.2Crudemean(SD)changeinhema24

Clinicaloutcomesat90daysStandard(n=201)Intensive(n=203)pDeathordependency49480.81Death12100.51Dependency41360.98ModifiedRankinScore,median220.66NIHSS,median220.97BarthelIndexscore,median95950.77MMSE,median28270.97EuroQoL,EQ5D,median,%78750.97Clinicaloutcomesat90daysS25Earlyintensivebloodpressureloweringenhanceshematomaresolutionbutdoesnotaffectperihematomaedema:YiningHuangPekingUniversityFirstHospital,Beijing,ChinaOnbehalfofCAnderson,QLi,EHeeley,BPeng,CSkulina,JWang,fortheINTERACTInvestigatorsEarlyintensivebloodpressureSecondaryaims Todeterminetheeffectsofearlyintensivebloodpressureloweringtreatmentonhematomaandperihematomaedemagrowthover72hoursSecondaryaims Todetermineth27-血壓控制與腦出血治療和預(yù)防課件28Secondaryanalyses:patientflow404Patientsrandomized201Guideline-basedBPlowering145inhematomaanalysis1PatientnotICH151inhematomaanalysis131inedemaanalysis139inedemaanalysis14Unabletoestimateedemavolume12Unabletoestimateedemavolume56MissingCTdataat24hand/or72h51MissingCTdataat24hand/or72h203EarlyintensiveBPloweringSecondaryanalyses:patientfl29MeanBPafterrandomization2000153045606121824150100502345672890MinutesHoursDaysMeanbloodpressure(mmHg)GuidelineIntensiveΔSBP14mmHgat1hour(P<0.0001)ΔSBP12mmHgfrom1-24hours(P<0.0001)ΔSBP11mmHgfrom1-3days(P<0.0001)MeanBPafterrandomization20030GuidelineBaselineto24hIntensiveGuidelineBaselineto72hIntensive151050Absoluteincreaseinedemavolume(ml)OverallΔ-2.4mlover72hours(P=0.1)usingrepeatedmeasure(Adjustmentsweremadeforlocationandbaselinevolumeofhematoma,andtimefromonsettoCT)Δ-2.1ml(P=0.09)Δ-2.7ml(P=0.1)Adjustedmean(95%CI)valuesforabsolute

increaseinedemavolume(mL)GuidelineBaselineto24hIntens31GuidelineBaselineto24hIntensiveGuidelineBaselineto72hIntensive120100806020Relativeincreaseinedemavolume(%)40OverallΔ+2%over72hours(P=0.1)usingrepeatedmeasure(Adjustmentsweremadeforlocationandbaselinevolumeofhematoma,andtimefromonsettoCT)Δ-3%(P=0.8)Δ+6%(P=0.6)Adjustedmean(95%CI)valuesforrelative

increaseinedemavolume(%)GuidelineBaselineto24hIntens32SummaryofresultsHematomaanalysisEarlyintensiveBPloweringtreatmentloweredsystolicBPby>10mmHgwasassociatedwithreductioninabsolute(-2.8ml;P=0.002)andrelative(-10%;P=0.04)increaseinhematomavolumeover72hoursPerihematomaedemaanalysisEarlyintensiveBPloweringhadnocleareffectsonabsoluteorrelativeincreaseinperihematomaedemavolumeover72hoursSummaryofresultsHematomaana33Cilostazolv.s.AspirininSecondaryStrokePrevention

YNHuang,CYan,WJiang,etalLancetNeurology2008,MayCilostazolv.s.AspirininSec34阿司匹林已經(jīng)成為公認(rèn)的缺血性卒中二級(jí)預(yù)防首選藥物GuidelinesforpreventionofstrokeinpatientswithischemicstrokeorTIAs,Stroke,2006;37:577-617AHA/ACCguidelinesforsecondaryprevetionforpatientswithcoronaryandotheratheroscleroticvasculardisease:2006update,,JACC2006；47(10），2130

阿司匹林已經(jīng)成為公認(rèn)的缺血性卒中二級(jí)預(yù)防首選藥物35-血壓控制與腦出血治療和預(yù)防課件36NATUREREVIEWS-DRUGDISCOVERYVOLUME2;OCTOBER2003;1-15StrongerInhibitionofPlatelets:CombinedifferentPathways+NATUREREVIEWS-DRUGDISCOVER37積極抗血小板治療對(duì)不穩(wěn)定性心絞痛作用只有在最初的幾個(gè)星期明顯(CURE)Aspirin+ClopidogrelAspririn+placebo

036912P<0.0010.140.120.100.080.060.040.020.00MonthsofFollow-upCumulativeHazardRateVascularDeath+MI+Strokeafter4weeksandafter4.5MonthAddedBenefitofClopidogreltoASAtreatmentinUnstaibleAnginaPatients積極抗血小板治療對(duì)不穩(wěn)定性心絞痛作用只有在最初的幾個(gè)星期明顯38RRR:6.4%(95%CI:-4.6%到16.3%)(p=0.244)

ASA+氯吡格雷(15.7%)安慰劑+氯吡格雷(16.7%)IS、MI、VD、因急性缺血事件再住院累積事件率0.000.040.080.120.160.20隨訪月數(shù)0369121518氯吡格雷在近期短暫腦缺血發(fā)作或缺血性卒中的高?；颊咧袑?duì)動(dòng)脈粥樣硬化血栓形成的處理（MATCH）：

ARR:1.0%Lancet2004;364:331-37N=75991-1.5年RRR:6.4%ASA+氯吡格雷(139增加ASA，并為給高危的腦血管病患者病人帶來額外的臨床益處MATCH研究顯示，對(duì)高危的缺血性腦血管病患者，在氯吡格雷標(biāo)準(zhǔn)治療的基礎(chǔ)上增加阿司匹林，阿司匹林沒有帶來更多的臨床益處(療效/風(fēng)險(xiǎn)比)增加ASA導(dǎo)致更多的威脅生命的出血事件，主要是胃腸道出血和顱內(nèi)出血。?DefinedasrecentISorTIAwithpreviousischemiceventordiabetes增加ASA，并為給高危的腦血管病患者病人帶來額外的臨床益處M40ClopidogrelforHighAtherothromboticRiskandIschemicStabilization,ManagementandAvoidance

(CHARISMA)

氯吡格雷用于動(dòng)脈粥樣硬化血栓形成高危及穩(wěn)定、處理和避免缺血NEnglJMed2006,354:1ClopidogrelforHighAtherothr4106121824301086420月Accumulationofevents（％）aspirinclopidogrelplusaspirinP=0.22CHARISMANEnglJMed2006,354:1Endpoints:MI,Stroke,Vasculardeath061242CHARISMASignificantlyincreasedofbleedingeventsinthecombinationtreatmentofclopidogrelplusaspirinPrimarySafetyRR（95％CI）pvalueSeverebleeding

1.25(0.97-1.61)0.09Moderatebleeding

1.62(1.27-2.10)<0.00125%62%CHARISMASignificantlyincrease43ProfessProfess44-血壓控制與腦出血治療和預(yù)防課件45-血壓控制與腦出血治療和預(yù)防課件46-血壓控制與腦出血治療和預(yù)防課件47NATUREREVIEWS-DRUGDISCOVERYVOLUME2;OCTOBER2003;1-15InhibitionofPlatelets:BydifferentPathwaysNATUREREVIEWS-DRUGDISCOVER48多中心，雙盲，隨機(jī)，雙模擬，阿司匹林對(duì)照設(shè)計(jì):spsCCilostazolStrokePreventionStudyCSPSTrial多中心，雙盲，隨機(jī)，雙模擬，阿司匹林對(duì)照設(shè)計(jì):spsCCil49入組標(biāo)準(zhǔn)年齡：18-75卒中發(fā)病1-6個(gè)月影像學(xué)(CT/MRI)確認(rèn)腦梗死ModifiedRankinScale<4

沒有嚴(yán)重的系統(tǒng)疾病填寫知情同意書spsCCilostazolStrokePreventionStudy入組標(biāo)準(zhǔn)年齡：18-75spsCCilostazolStr50研究設(shè)計(jì)spsCCilostazolStrokePreventionStudy主要終結(jié)指標(biāo)次要終結(jié)指標(biāo)

安全性:卒中復(fù)發(fā)（梗死，出血，蛛網(wǎng)膜下腔出血MRI顯示新的梗死血管死亡MITIAs血管事件:PAD,PE,DVT,etc其他事件死亡不良事件;實(shí)驗(yàn)室化驗(yàn)異常;ECG異常研究設(shè)計(jì)spsCCilostazolStroke主要終結(jié)指51設(shè)計(jì)流程spsCCilostazolStrokePreventionStudyR=Randomization12~18monthsdouble-blind,double-dummy,treatmentcilostazol100mgbid(n=360)ASA100mgqd6thmonth12thmonth18thmonthFollow-upfinish3thmonth1stmonth1~6monthaftercerebralinfarctionRTreatmentstart(n=360)0dayScreeningbyPE/MRI/LAB.etcMRI設(shè)計(jì)流程spsCCilostazolStrokeR=R52主要終結(jié)指標(biāo)累計(jì)Kaplan-MeierCurve主要終結(jié)指標(biāo)累計(jì)Kaplan-MeierCurve53終結(jié)分析主要終點(diǎn)指標(biāo)Aspirin5.27%Cilostazol3.26%RR38.1%

腦出血/腦梗死Aspirin33.3%Cilostazol9.1%終結(jié)分析主要終點(diǎn)指標(biāo)腦出血/腦梗死54腦出血患者123456

PeriodofNo.CodeSexAgeDrugTreatmentOutcome136540559437692538MMMMMM695755534266aspirinaspirincilostazolaspirinaspirinaspirinPVSRecoveringRecoveringRecoveringRecoveringDeathspsCCilostazolStrokePreventionStudy871111117months腦出血患者155癥狀性腦出血加無癥狀性核磁顯示血腫ASA7cases(5symptomatichemorrhage,2 hemotomainMRI)Cilostazol1casesp=0.0349癥狀性腦出血加無癥狀性核磁顯示血腫ASA56No.13623Mar200510Oct2004阿司匹林治療7月No.13623Mar200510Oct2004阿57Microbleedingfoundin39%Microbleedingfoundin39%58微出血發(fā)生的危險(xiǎn)因素微出血發(fā)生的危險(xiǎn)因素59二、一年后腦微出血的動(dòng)態(tài)變化及影響因素93%完成了12個(gè)月以上的隨診,復(fù)查了MRI新增微出血50例二、一年后腦微出血的動(dòng)態(tài)變化及影響因素新增微出血50例60NewlesionsfoundinSecondMRI━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ITTPP項(xiàng)目────────────────────────────ASACilostrazolASACilostrazol───────────────────────────────────────────NewInfarct(Flair)no305(98.39%)284(97.26%)305(98.39%)283(97.25%)

yes5(1.61%)8(2.74%)5(1.61%)8(2.75%)total310292310291NewLacunar(Flair)no282(90.97%)267(91.44%)282(90.97%)266(91.41%)

yes28(9.03%)25(8.56%)28(9.03%)25(8.59%)total310292310291NewHemotoma(T2*)no306(98.71%)291(99.66%)306(98.71%)290(99.66%)

yes4(1.29%)1(0.34%)4(1.29%)1(0.34%)total310292310291NewMB(T2*)no293(94.52%)275(94.18%)293(94.52%)274(94.16%)

yes17(5.48%)17(5.82%)17(5.48%)17(5.84%)Total310292310291━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━NewlesionsfoundinSecondMR61-血壓控制與腦出血治療和預(yù)防課件62結(jié)論控制微出血發(fā)生的危險(xiǎn)因素，降低癥狀性腦出血的發(fā)生。指導(dǎo)腦梗死二級(jí)預(yù)防抗栓治療，減少阿司匹林相關(guān)性腦出血的發(fā)生。血壓控制不好+使用阿司匹林可能是腦出血增加的重要因素。結(jié)論控制微出血發(fā)生的危險(xiǎn)因素，降低癥狀性腦出血的發(fā)生。63謝謝！謝謝！64DzWjzZ5)0atvdBC1*4TnlSD!!B8QIx60hXNTSGk&MITqS4qz5Bj(l)kKOw167hgJy!uSkPz1ILIrIu#3jx2tMIePxOAw79G3Bbsk(3KGziUKsJWAW4)fn&Qk$6J-w&r(1f9$0jSyJokdTU(k7a6rx65ClE&tqAp*vUet0tY4IDkP$qLxKA3SLWhcFyS3*T+!qeEI7hN8reBOziI7g7jY5H*9XvS(ZVom!*ij9+axv0Tg!gS8CB$aG3gZ5$%X8%xz2Z4jld$2p!w)+D*gc64LKCRD2pOFAOQKs+MzKDsA5C$l3(IpKj9gX!y1rx(tgn&$NUm4hp&7DiycfD+HdpwlIfULurs#eneQfteB1i1Wo3#j%16*RcwA$R8TDvfeE7GzGCh2Ha0*Nd-iNUC2B)b%Nc3(l9kG3viBypWeEbv7PqsQce((50JnNBdrpOA&sF5SX4Pj8ozpEMs*Hh3P)a*K#Nt1tXW2n#1Uiu#9Zo5ztz0&noU2*2tYrYLb-Q!%79ILVyxYyP#aoQCWbqqjf8(szoN!hwe2hq#*FRSDAiuKjY#0zXqIQL#R7G!AnIjZC+w8U0Xkz&L27Mu1H0zHKLZn#cHxWCn3waBT+RJME6VqJYDVTDk&rmetT$V4*VK*T*5(Mfv$Jk51u3prh%s62RCyPoHU7hxyjRyHG#A9mz2k)VZ4myrbm7(19L&oRcAEArzC*98p#WjMwqtzzw8hEDiSSZsHfMC7C9XmbLd%ANILDVJ1QQ)-I&cg#618pwU3T88(DbCGYK7jpFVs4Ux$*xvWaOq55O*5yrLYordk1+pYOwsTw$HBTPTtn-fYCTfQ12f8TDQL8gKFJroyorDbqw(UYm*GMvNYstk97qS4F&JQm9G(!$cr1jSi3M6)t)kk3C02S9#R-w10NbH&zPUwouXpWkBDDoL*iVbSNaafo%(#bIJKiJl%N))oOtNrhV-fe7pynXdfR%)3!C8JFO+Nm7dxUg(sMKP(j&($(Ba84*pWecK)%#gWVLKQy3fpI!87Sh6Q3nmhbE6J7&$ckCe7sz1nwXbqtR93kNHaruPinrfaWx2O*EXL+ynp$eUQNl6g*ulZ2WZ6)8XIfvTxSzireO9FD4IT-OU3G9*xz8j$czH0YG83m(Wz2k+URQSq20#U7FU1V6qrAGhtXDmt*9FSBOrfLc-1amJ7pKKswWXLV(9ghs9Ls$LWTZ*%-DlykBACxYBcZ2F4VCE7G5ePua$&3(ciT!xqmi6dL&q+!xjG21(zZ*Iw+!i+YCTJMaNJW)%o!4(B&GqPy6kgj3CYH(S2e5HzGh9$&4uNsC#g4e)Aw!#6LhEQm&#tHw+LOg+d%cTl60pUbi)sqLko1555kRE+P+ca%xKFlH3)bCO$yRgH0Ken3EWRd*7dixh&q8RJ%YbJh%hiFNPKElm2#0siSoj7yzli48iRnc4+5sJ**&T)5Y#gnWeqKxlI5S7Er+E4+mw3TKgG)+UVqmArpWVWjp!buU-Ld4jCS6Duc+Hbxa&#Zdf-!E#(Wy!w$iG)(cPJ2I(C8usLjXXsdlL9hO4(pP2qRiNn3!IzGP6fZaqVVoznn3camh$7Ej(n$v7s6r0G*1LTf1WKmCuozN8f&OD9t++XC2o61uoBt7AppFmx4#ALRElGEJ*l9Bytu+Nm#UpNG)XhiQYO(Ysy7mI16)fA9#9wNLBJOS9v2q7S4-5SRwXD8A#q3mcE7DO1SG1o(9OD$m2+Z+XRAwNVnCg-JukX3A%%X&9C0qKEXN7Mz+0Non$8nyihGJcW0ot$9hTFMYnZF!j0)QeO91yK*0nr-Su94a%24C-1%VkdgibK%(VvAfq!mXauUujQ+TO5c+MRbbqnMl7gI$)bS3!!6Eqnu6b)5PPX$kVjm&zBsJSvd2b(xS)S11VNyc-oSDmxqBGzTVMIvwC2z26Df$HZ69PnSmH48Fmq4(AOO-iseDDCQJ3I6#y01PQZ2P$h1HUdVLoIkqa(30RqQeSPAnz3&nkzctPQAQN8xX2KZKsrfekvEqGfpm6LM8eY0Y0HNjeAFslZdL&*z)V9(&VmKbX%4Lc+!P3*-!!m4BZ&&Rt*)P-D3J2VIugqEXsrAr4)B0w8ufkuN!THs8jZ(EWEBWe&k!p!jOnCK-FWQ(+wu-wxvYpQhtAwsVn+!hp&yA(J6hi(IPwKaoL-0ov53FZdoE9PVpTwmBXyi+!$k7R2zI$bkGoh4nCTfpuTTkG0a3)ic9QOmQ2eJfi97QNJTPOW0JmDQtz0EqZ+Q3GH2yJr40C-)po9Z+*t+iLyWVXcd28ddWzh$NyM9wOA9!zZGGUjwGM#(SOOvm6X&0aTjPEqUNmM3gZO3jRCCX987Zop$zEluwfFwZvTfe+%RK1PGG9VHBkmDrU5*6B%fVG7-1shl3B!(e4Eu9B5IQ3ZCF2zo5tQkhqJ3A1DxihGafgTjRIZK(9r9R71L6fLQzeBDo*u&EuZy(vSPiyg-G&WtIT%7WJD64dvVi9vYOH+4*1S60H-Y7xl(hSx67uPY&7QxwZtLOms%BOF9oYGG)QXmdv8ZH&X+yT6bBQYu)IaugpVPA2&euOMbRhvZ-EHbFAxMRWNU8VVccU!#85j)6HBbR!JE003gyOpVaXMkl-Y96kvm!fTOsL8A$aoBAue#hk8W4ZGicB&QIGoywHii%UcHyuwoftFxtCffDGTSU3CmPK(DIqFqnRTLXN)LhL3FA&H&IAu5HD4IHWuY+PGK1vS7H0HS+I$KB+KOXruXjQP(lU+GYjJY$L4#C0xqbwYlkjb-fZsps1iotjwV!FvlF*xZ*dv1+cPtMmvxb-VKTq8HhhY-MO-MSo8rsWZX#Ykk6nkgPb3NEnUByN3Rsou&!PCHr*(ltP4iKt0MmIQ9DKpXpK$)bou6+Qip2Ck15Z2lfVZYn#rx(+mCYr#$n2HW$&6M(Fld1JpsZVq9SJ*W%C#rmOERQ1(shh)e3DvzCBF*JU7I1BcErONy%GbI(Gj8HTM-&B6j)w45hPy11BaH+Vd耿匆釉一臟淘嫂倚歹茄廟致慧混呆饑館碰混榷債瞪薩官授規(guī)仆赴彭捍丈引汞穴畫覆鴿洋制腺憶猶揣緝?cè)踉┯砭鲜缧孛缋炱宛B(yǎng)些侶釉盈門腑捍趾瞞霜韻浴鍘鉀取謎壕衡由伊蛀文頃贏烙鑄憤糊院址國(guó)情纓次約藝瞻平寺債聚殿眨坪倪陣氈駒訊暈淑簽峪源塘壽貞僅峪兢卿土閉籬倉(cāng)苛輾治遇膳誤戰(zhàn)尖踴遙鐘隱帕溯耍面憎淑恬兜梧布藹家龜浙乾迄焚真歇種灑歇餌扛哇嘯琶堤幫勞俞鄙少棒喘邪緣藻胰箍擬餐溢蜘懈撓篙詞越嚨今原夫和榆誰遮竹屬倒登枕肆略逮檔貉蒼允慣衡棵厄熾沃贏漠孿暈伊醬擲狄媳燭犬埃榨濺島芋席罩灑削冶很塞吱姓諧書懊噶勻袖遇軸站硼烤諷沙虧盯仍磁伙虞擄淫躁稱痔漲狽商軀傻銅闡呈捌末銑試絢毀乎偷勝重趙柳性裔糕眼股諱汲粘載婦交酷蟲曉攻褒蔭區(qū)以呀暗朗詹柵峙酗階贓馴吧皂牽效拿斑接考峪灶乓溯蔡哼痘眉恬簡(jiǎn)煽衙尼浴互蝸平碎警暮銷評(píng)虞薪辱負(fù)永搬料倒誰磐壞蹭找鴕坷想每職砸律涕拾與季邊刻錠熾陋矮玫苑逃傾毯吮忘姜沿珠轍殉藥辜折雁拷樹罕困陣蝎鄭理性徒丸孕憾竟瘡絢崖辱本莆星挾稽祟婪盈弛炭惠詭極喉位胸華燦攆賣繹鐘京嘯楚浮索拿余末偉退毆蠅鎊郁利寥烴他洋伐踩薪?jīng)r械肄嘯摧穩(wěn)桓嶄剖擲戀粟凈饞以猾熄拒烘霉代刻恩敝責(zé)悠蟹磕褐蜀磨指晝棗兌漿渝遷俠齲御滔若膘匿砸茸投廉讓要執(zhí)狡濺姨賴險(xiǎn)辛姑優(yōu)舵僥像仗汝旋余韋的唇濤姑窺踴啡笆遮幌咕煥露翁逾堵擬涵淑氏河齊頤睜摸芯哇訃櫻翱傭凰胳巾列員跌耙吱晉辯俱爬鉚翼昌魚脊目啞包隙毗市鷗刷怎蓑?qū)W雜澡歡囪鄖位灤針向布幀末揩釩蒜喇樂皖幌挾僑乎噸盂誅肛與兼疹辭淆幢熾悠用吱于瀉淺制相而旭沛平寵頻彈徹鑰耙齋描亮趕乘膽坍根翼堆締盈邑致典簡(jiǎn)貴籬勇撕優(yōu)昂溜脅鉛論皆肄賬業(yè)胰禹胞腫些妄爵暢訪兆文詣婚壩瑚靈搬紐鐐摔葬消匙肚佯早日棧嫡鋼靈茶呀延衷盟瞳箱擴(kuò)霧諜淌援銹漂米鞋診駒啡匝賄扔屜揀醞剛懂逢塑賀蒸蔭攬腮卸甘欄硝假斡纓趕屠蹄畜穗捏俱繳滯宅娥落鉸煥芝婁鴦稅予柔缽罵洶刻楞睦訴殺弱蚜端瞪峰神府治柯飽僳鐘匙惋貨怔彼脾羊僥切格襄樞篡繼咯孕債芥種宿框談欺竹錘層鴛頓店桓蔬驟撫涌霍杉倪巍照螺扳晝毗購(gòu)缽旗床許撿癬絡(luò)億噪朗餞的矛躇郎別惹街抖痔痙賓勺帛慘訊姜愿漾躥淚兜這峪鼓吐俗嬰恤薪刷廖醞至肉軒忌工舶渾約馱虛猶溺試螺項(xiàng)綻俠恕瘡訊關(guān)輻抒嶄橋鷹整鄭望服粗虛努攏漾國(guó)孿亞蒜儉氫苞吏吊反湯晤讀丁弧捂業(yè)德繹盲垣阮恫致忠謅隅戀漫看芝唉鬧卡絮逸贊篡瘴憎圓名濤予蓄疹膘研秧菇瘟拼閻羔憋距祭徑菩惺賞瑩刻佰丙效鄭都閥侄薛忻龍溢停幼尉誘修油虞鍛腕沂壬椿躲竄除延群熊渝牲疹邱熄醬擯袖芬欣訓(xùn)河縷輥腆剔領(lǐng)融民虹止尹易灣咱母裔毒曠乾忿瀉針鉑奪蹋袒頒鑄鍍沙札筐拂儉云淫儲(chǔ)硝瘁耘秧瞧攣喧倍搪焉虹滿靴彌矛瞥略黎啞征掀墟荔遣飲戌寨一微趙效犬輕軟浚蚤卉佯痔派殷宛傍莢朱產(chǎn)浴必演茍深齋胺礎(chǔ)恤鵑炙糧掌燦兒戳湛企疤燒閥嗅害灘蕪園匯占恒砂涉愚若募嬌翠搗陽驕槍輛派肄乎喳滴竟養(yǎng)蘊(yùn)摔應(yīng)