Exercise for depression

160 Pages·2013·0.96 MB·English

Exercise for depression (Review)
Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE
ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary
2013,Issue9
http://www.thecochranelibrary.com
Exercisefordepression(Review)
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 26
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Analysis1.1.Comparison1Exerciseversus’control’,Outcome1Reductionindepressionsymptomspost-treatment. 117
Analysis1.2.Comparison1Exerciseversus’control’,Outcome2Reductionindepressionsymptomsfollow-up. . . 119
Analysis1.3.Comparison1Exerciseversus’control’,Outcome3Completedinterventionorcontrol. . . . . . . 120
Analysis1.4.Comparison1Exerciseversus’control’,Outcome4Qualityoflife. . . . . . . . . . . . . . 122
Analysis2.1.Comparison2Exerciseversuspsychologicaltherapies,Outcome1Reductionindepressionsymptomspost-
treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Analysis2.2.Comparison2Exerciseversuspsychologicaltherapies,Outcome2Completedexerciseorpyschological
therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Analysis2.3.Comparison2Exerciseversuspsychologicaltherapies,Outcome3Qualityoflife. . . . . . . . . 125
Analysis3.1.Comparison3Exerciseversusbrightlighttherapy,Outcome1Reductionindepressionsymptomspost-
treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Analysis4.1.Comparison4Exerciseversuspharmacologicaltreatments,Outcome1Reductionindepressionsymptoms
post-treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Analysis 4.2. Comparison 4 Exercise versus pharmacological treatments, Outcome 2 Completed exercise or
antidepressants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Analysis4.3.Comparison4Exerciseversuspharmacologicaltreatments,Outcome3QualityofLife. . . . . . . 128
Analysis5.1.Comparison5Reductionindepressionsymptomspost-treatment:Subgroupanalyses,Outcome1Exercisevs
controlsubgroupanalysis:typeofexercise. . . . . . . . . . . . . . . . . . . . . . . . . 129
Analysis5.2.Comparison5Reductionindepressionsymptomspost-treatment:Subgroupanalyses,Outcome2Exercisevs
controlsubroupanalysis:intensity. . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Analysis5.3.Comparison5Reductionindepressionsymptomspost-treatment:Subgroupanalyses,Outcome3Exercisevs
controlsubroupanalysis:numberofsessions. . . . . . . . . . . . . . . . . . . . . . . . 133
Analysis5.4.Comparison5Reductionindepressionsymptomspost-treatment:Subgroupanalyses,Outcome4Exercisevs
controlsubroupanalysis:diagnosisofdepression. . . . . . . . . . . . . . . . . . . . . . 135
Analysis5.5.Comparison5Reductionindepressionsymptomspost-treatment:Subgroupanalyses,Outcome5Exercisevs
controlsubgroupanalysis:typeofcontrol. . . . . . . . . . . . . . . . . . . . . . . . . 137
Analysis6.1.Comparison6Exerciseversuscontrol:sensitivityanalyses,Outcome1Reductionindepressionsymptoms
post-treatment:peer-reviewedjournalpublicationsanddoctoralthesesonly. . . . . . . . . . . . . 139
Analysis6.2.Comparison6Exerciseversuscontrol:sensitivityanalyses,Outcome2Reductionindepressionsymptoms
post-treatment:studiespublishedasabstractsorconferenceproceedingsonly. . . . . . . . . . . . . 141
Analysis6.3.Comparison6Exerciseversuscontrol:sensitivityanalyses,Outcome3Reductionindepressionsymptoms
post-treatment:studieswithadequateallocationconcealment. . . . . . . . . . . . . . . . . . 142
Exercisefordepression(Review) i
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Analysis6.4.Comparison6Exerciseversuscontrol:sensitivityanalyses,Outcome4Reductionindepressionsymptoms
post-treatment:studiesusingintention-to-treatanalysis. . . . . . . . . . . . . . . . . . . . 143
Analysis6.5.Comparison6Exerciseversuscontrol:sensitivityanalyses,Outcome5Reductionindepressionsymptoms
post-treatment:studieswithblindedoutcomeassessment. . . . . . . . . . . . . . . . . . . 144
Analysis6.6.Comparison6Exerciseversuscontrol:sensitivityanalyses,Outcome6Reductionindepressionsymptoms
post-treatment:allocationconcealment,intention-to-treat,blindedoutcome. . . . . . . . . . . . . 145
Analysis6.7.Comparison6Exerciseversuscontrol:sensitivityanalyses,Outcome7Reductionindepressionsymptoms
post-treatment:Lowestdoseofexercise. . . . . . . . . . . . . . . . . . . . . . . . . . 146
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 156
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Exercisefordepression(Review) ii
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Exercise for depression
GaryMCooney1,KerryDwan2,CarolynAGreig3,DebbieALawlor4,JaneRimer5,FionaRWaugh6,MarionMcMurdo7,GillianE
Mead8
1DivisionofPsychiatry,RoyalEdinburghHospital,NHSLothian,Edinburgh,UK.2InstituteofChildHealth,UniversityofLiverpool,
Liverpool,UK.3UniversityofBirmingham,Birmingham,UK.4MRCCentreforCausalAnalysesinTranslationalEpidemiology,School
ofSocialandCommunityMedicine,UniversityofBristol,Bristol,UK.5UniversityHospitalsDivision,NHSLothian,Edinburgh,UK.
6GeneralSurgery,NHSFife,VictoriaHostpitalKirkcaldy,Kirkcaldy,UK.7CentreforCardiovascularandLungBiology,Divisionof
MedicalSciences,UniversityofDundee,Dundee,UK.8CentreforClinicalBrainSciences,UniversityofEdinburgh,Edinburgh,UK
Contactaddress:GillianEMead,CentreforClinicalBrainSciences,UniversityofEdinburgh,RoomS1642,RoyalInfirmary,Little
FranceCrescent,Edinburgh,EH164SA,[email protected]@staffmail.ed.ac.uk.
Editorialgroup:CochraneDepression,AnxietyandNeurosisGroup.
Publicationstatusanddate:Newsearchforstudiesandcontentupdated(nochangetoconclusions),publishedinIssue9,2013.
Reviewcontentassessedasup-to-date: 13July2012.
Citation: Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J,Waugh FR, McMurdo M, Mead GE. Exercisefor depression.
CochraneDatabaseofSystematicReviews2013,Issue9.Art.No.:CD004366.DOI:10.1002/14651858.CD004366.pub6.
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Depressionisacommonandimportantcauseofmorbidityandmortalityworldwide.Depressioniscommonlytreatedwithantide-
pressants and/or psychological therapy,butsome peoplemaypreferalternativeapproachessuch asexercise.Thereare anumber of
theoreticalreasonswhyexercisemayimprovedepression.Thisisanupdateofanearlierreviewfirstpublishedin2009.
Objectives
To determine the effectiveness of exercise in the treatment of depression in adults compared with no treatment or a comparator
intervention.
Searchmethods
WesearchedtheCochraneDepression,AnxietyandNeurosisReviewGroup’sControlledTrialsRegister(CCDANCTR)to13July
2012.Thisregisterincludesrelevantrandomisedcontrolledtrialsfromthefollowingbibliographicdatabases:TheCochraneLibrary
(allyears);MEDLINE (1950 todate);EMBASE(1974todate)andPsycINFO (1967 todate).Wealsosearchedwww.controlled-
trials.com, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. No date or language restrictions were
appliedtothesearch.
WeconductedanadditionalsearchoftheCCDANCTRupto1stMarch2013andanypotentiallyeligibletrialsnotalreadyincluded
arelistedas’awaitingclassification.’
Selectioncriteria
Randomisedcontrolledtrialsinwhichexercise(definedaccordingtoAmericanCollegeofSportsMedicinecriteria)wascomparedto
standardtreatment,notreatmentoraplacebotreatment,pharmacologicaltreatment,psychologicaltreatmentorotheractivetreatment
inadults(aged18andover)withdepression,asdefinedbytrialauthors.Weincludedclustertrialsandthosethatrandomisedindividuals.
Weexcludedtrialsofpostnataldepression.
Exercisefordepression(Review) 1
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Datacollectionandanalysis
Tworeviewauthorsextracteddataonprimaryandsecondaryoutcomesattheendofthetrialandendoffollow-up(ifavailable).We
calculatedeffectsizesforeachtrialusingHedges’gmethodandastandardisedmeandifference(SMD)fortheoverallpooledeffect,
usingarandom-effectsmodelriskratiofordichotomousdata.Wheretrialsusedanumberofdifferenttoolstoassessdepression,we
includedthemainoutcomemeasureonlyinthemeta-analysis.Wheretrialsprovidedseveral’doses’ofexercise,weuseddatafromthe
biggest ’dose’of exercise,andperformedsensitivity analysesusing thelower’dose’.Weperformedsubgroup analysestoexplore the
influenceofmethodofdiagnosisofdepression(diagnosticintervieworcut-offpointonscale),intensityofexerciseandthenumberof
sessionsofexerciseoneffectsizes.Twoauthorsperformedthe’Riskofbias’assessments.Oursensitivityanalysesexploredtheinfluence
ofstudyqualityonoutcome.
Mainresults
Thirty-ninetrials(2326participants)fulfilledourinclusioncriteria,ofwhich37provideddataformeta-analyses.Thereweremultiple
sourcesofbiasinmanyofthetrials;randomisationwasadequatelyconcealedin14studies,15usedintention-to-treatanalysesand12
usedblindedoutcomeassessors.
Forthe35trials(1356participants)comparingexercisewithnotreatmentoracontrolintervention,thepooledSMDfortheprimary
outcomeofdepressionattheendoftreatmentwas-0.62(95%confidenceinterval(CI)-0.81to-0.42),indicatingamoderateclinical
effect.Therewasmoderateheterogeneity(I²=63%).
Whenweincludedonlythesixtrials(464participants)withadequateallocationconcealment,intention-to-treatanalysisandblinded
outcomeassessment,thepooledSMDforthisoutcomewasnotstatisticallysignificant(-0.18, 95%CI-0.47to0.11).Pooleddata
fromtheeighttrials(377participants)providinglong-termfollow-updataonmoodfoundasmalleffectinfavourofexercise(SMD-
0.33,95%CI-0.63to-0.03).
Twenty-ninetrialsreportedacceptabilityoftreatment,threetrialsreportedqualityoflife,nonereportedcost,andsixreportedadverse
events.
For acceptability oftreatment(assessedbynumber ofdrop-outs duringtheintervention), theriskratiowas1.00(95% CI0.97to
1.04).
Seventrialscomparedexercisewithpsychologicaltherapy(189participants),andfoundnosignificantdifference(SMD-0.03,95%
CI-0.32to0.26).Fourtrials(n=300)comparedexercisewithpharmacologicaltreatmentandfoundnosignificantdifference(SMD
-0.11,-0.34,0.12).Onetrial(n=18)reportedthatexercisewasmoreeffectivethanbrightlighttherapy(MD-6.40,95%CI-10.20
to-2.60).
Foreachtrialthatwasincluded,twoauthorsindependentlyassessedforsourcesofbiasinaccordancewiththeCochraneCollaboration
’Riskofbias’tool.Inexercisetrials,thereareinherentdifficultiesinblindingboththosereceivingtheinterventionandthosedelivering
theintervention.Manytrialsusedparticipantself-reportratingscalesasamethodforpost-interventionanalysis,whichalsohasthe
potentialtobiasfindings.
Authors’conclusions
Exerciseismoderatelymoreeffectivethanacontrolinterventionforreducingsymptomsofdepression,butanalysisofmethodologically
robusttrialsonlyshowsasmallereffectinfavourofexercise.Whencomparedtopsychologicalorpharmacologicaltherapies,exercise
appearstobenomoreeffective,thoughthisconclusionisbasedonafewsmalltrials.
PLAIN LANGUAGE SUMMARY
Exercisefordepression
Whyisthisreviewimportant?
Depressionisacommonanddisablingillness,affectingover100millionpeopleworldwide.Depressioncanhaveasignificantimpact
onpeople’sphysicalhealth,aswellasreducingtheirqualityoflife.Researchhasshownthatbothpharmacologicalandpsychological
therapiescan beeffectiveintreating depression. However,many peoplepreferto tryalternative treatments. SomeNHS guidelines
suggestthatexercisecouldbeusedasadifferenttreatmentchoice.However,itisnotclearifresearchactuallyshowsthatexerciseisan
effectivetreatmentfordepression.
Exercisefordepression(Review) 2
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Whomaybeinterestedinthisreview?
Patientsandfamiliesaffectedbydepression.
GeneralPractitioners.
Mentalhealthpolicymakers.
Professionalsworkinginmentalhealthservices.
Whatquestionsdoesthisreviewaimtoanswer?
ThisreviewisanupdateofapreviousCochranereviewfrom2010whichsuggestedthatexercisecanreducesymptomsofdepression,
buttheeffectwassmallanddidnotseemtolastafterparticipantsstoppedexercising.
Wewantedtofindoutifmoretrialsoftheeffectofexerciseasatreatmentfordepressionhavebeenconductedsinceourlastreview
thatallowustoanswerthefollowingquestions:
Isexercisemoreeffectivethannotherapyforreducingsymptomsofdepression?
Isexercisemoreeffectivethanantidepressantmedicationforreducingsymptomsofdepression?
Isexercisemoreeffectivethanpsychologicaltherapiesorothernon-medicaltreatmentsfordepression?
Howacceptabletopatientsisexerciseasatreatmentfordepression?
Whichstudieswereincludedinthereview?
Weusedsearchdatabases tofindallhigh-quality randomisedcontrolledtrialsofhoweffectiveexerciseisfortreating depressionin
adultsover18yearsofage.WesearchedforstudiespublishedupuntilMarch2013.WealsosearchedforongoingstudiestoMarch
2013.Allstudieshadtoincludeadultswithadiagnosisofdepression,andthephysicalactivitycarriedouthadtofitcriteriatoensure
thatitmetwithadefinitionof‘exercise’.
Weincluded39studieswithatotalof2326participantsinthereview.Thereviewersnotedthatthequalityofsomeofthestudieswas
low,whichlimitsconfidenceinthefindings.Whenonlyhigh-qualitytrialswereincluded,exercisehadonlyasmalleffectonmood
thatwasnotstatisticallysignificant.
Whatdoestheevidencefromthereviewtellus?
Exerciseismoderatelymoreeffectivethannotherapyforreducingsymptomsofdepression.
Exerciseisnomoreeffectivethanantidepressantsforreducingsymptomsofdepression,althoughthisconclusionisbasedonasmall
numberofstudies.
Exerciseisnomoreeffectivethanpsychologicaltherapiesforreducingsymptomsofdepression,althoughthisconclusionisbasedon
smallnumberofstudies.
The reviewers also note that when only high-quality studies were included, the difference between exercise and no therapy is less
conclusive.
Attendanceratesforexercisetreatmentsrangedfrom50%to100%.
Theevidenceaboutwhetherexercisefordepressionimprovesqualityoflifeisinconclusive.
Whatshouldhappennext?
Thereviewersrecommendthatfutureresearchshouldlookinmoredetailatwhattypesofexercisecouldmostbenefitpeoplewith
depression,andthenumberanddurationofsessionswhichareofmostbenefit.Furtherlargertrialsareneededtofindoutwhether
exerciseisaseffectiveasantidepressantsorpsychologicaltreatments.
Exercisefordepression(Review) 3
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
CopyrighxerciseE SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation]
tfo
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hn Symptomsofdepression The mean symptoms of de- The mean symptoms of de- 1353 ⊕⊕⊕(cid:13) SMD-0.62(95%CI:-0.81to-
W Differentscales pressioninthecontrolgroups pression in the intervention (35studies) moderate2,3,4 0.42).
iley Follow-up:post-treatment was groupswas Theeffectsizewasinterpreted
&
S 0 0.62 standard deviations as ’moderate’ (using Cohen’s
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td
.
Symptoms of depression The mean symptoms of de- The mean symptoms of de- 377 ⊕⊕(cid:13)(cid:13) SMD-0.33(95%CI:-0.63to-
(long-term) pression (long-term) in the pression(long-term)inthein- (8studies) low4,5 0.03).
differentscales controlgroupswas terventiongroupswas Theeffectsizewasinterpreted
0 0.33 standard deviations as’small’(usingCohen’sruleof
lower thumb)
(0.63to0.03lower)
Adverseevents Seecomment Seecomment 0 ⊕⊕⊕(cid:13) Seven trials reported no dif-
(6studies) moderate ferenceinadverseeventsbe-
tweenexerciseandusualcare
groups. Dunn 2005 reported
increased severity of depres-
sivesymptoms(n=1),chest
pain (n = 1) and joint pain/
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opyrighxercise swelling (n = 1); all these
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2013depre cise.Singh1997reportedthat
Ts 1exerciserwasreferredtoher
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ochra(Revie tmouisnccurleoasskienlgetaslusicyimdaplittoym; sanidn
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atio reportedadverseeventsinde-
n. tail (visits to a health profes-
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u sional, minor illness, muscu-
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lish lar pain, chest pain, injuries
e
d requiring training adjustment,
b
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hn and found no difference be-
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tween the groups. Knubben
ile
y 2007 reported ‘‘no negative
&
S effects of exercise (muscle
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ns pain,tightnessorfatigue)’’;af-
,
Ltd terthetraininghadfinished,1
. person in the placebo group
required gastric lavage and 1
person in the exercise group
inflictedasuperficialcutonher
arm.Sims2009
reported no adverse events
or falls in either the exercise
or control group. Blumenthal
2007 reported more side ef-
fects in the sertraline group
(see comparison below) but
there was no difference be-
5
CE
opyrighxercise tweentheexerciseandcontrol
tfo
©r group. Blumenthal 2012a re-
2013depre ported more fatigue and sex-
Ts ualdysfunctioninthesertraline
heCsion groupthantheexercisegroup
o(R
chraneview Acceptabilityoftreatment Studypopulation 1363 ⊕⊕⊕(cid:13) RR1
eC) (29studies) moderate2 (95%CI:0.97to1.04)
olla 865per1000 865per1000
bo (839to900)
r
a
tio
n. Qualityoflife Themeanqualityoflifeinthe 0 Seecomment Therewasnostatisticallysig-
P
u interventiongroupswas (4studies) nificant differences for the
b
lish 0higher mental (SMD-0.24;95%CI-
e
d (0to0higher) 0.76 to 0.29). psychological
b
yJo (SMD0.28;95%CI-0.29to0.
hn 86)andsocialdomains(SMD
W
0.19; 95% CI -0.35 to 0.74)
ile
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o
ns for the environment domain
,
Ltd favouringexercise(SMD0.62;
. 95% CI 0.06 to 1.18) and 4
studiesreportedastatistically
significant difference for the
physicaldomainfavouringex-
ercise (SMD 0.45; 95% CI 0.
06to0.83)
*Thebasisfor the assumedrisk(e.g.themediancontrol groupriskacross studies) isprovidedinfootnotes. Thecorresponding risk(andits95%confidence interval) isbasedonthe
assumedriskinthecomparisongroupandtherelativeeffectoftheintervention(andits95%CI).
CI:Confidenceinterval;RR:Riskratio;
GRADEWorkingGroupgradesofevidence
Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect.
Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate.
Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate.
Verylowquality:Weareveryuncertainabouttheestimate.
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2013depre 2LeasctkimoafteblionnditnhgeoHfDoRuStc.omeassessorsprobablyincreasedeffectsizesanddrop-outrateswerehigh.Alsosequencegenerationwas
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chraneview 45PLaocpkuloaftiobnlinsdizinegisolfaorguetc,oemffeecatsssizeessisorasbopvroeb0a.b2lySDin,carenadstehdee9f5fe%ctCsIizdeosesanndotdcrorops-osuttheraltiensewofenreoheifgfehc.tA.lsosequencegenerationwas
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