5/7/2017 Drugtreatmentofvertigoinneurologicaldisorders:<b>IvanaIBerisavac,AleksandraMPavlovi,JasnaJ.ZidvercTrajkovi,NadedaM.ovikoviterni,LjiljanaG.

BeslaBumbairevi</b>,Neurololy

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COMMENTARY
Year:2015|Volume:63|Issue:6|Page:933939

Drugtreatmentofvertigoinneurologicaldisorders
IvanaIBerisavac,AleksandraMPavlovi,JasnaJ.ZidvercTrajkovi,NadedaM.ovikoviterni,LjiljanaG.BeslaBumbairevi
SchoolofMedicine,UniversityofBelgradeNeurologyClinic,ClinicalCenterofSerbia,Belgrade,Serbia

CorrespondenceAddress:
IvanaIBerisavac
TomaaJeaNo.5,FN211648,Belgrade
Serbia

Abstract
Vertigoisacommonsymptomineverydayclinicalpractice.Thetreatmentdependsonthespecificetiology.Vertigomaybesecondarytoinnerearpathology,or
anyexistingbrainstemorcerebellarlesionbutmayalsobepsychogenic.Centralvertigoisaconsequenceofacentralnervoussystemlesion.Itisoften
associatedwithafocalneurologicaldeficit.Peripheralvertigoissecondarytodysfunctionoftheperipheralvestibularsystemandisusuallycharacterizedbyan
acutevertigowithlossofbalance,sensationofspinninginthespaceoraroundself,andisexaggeratedwithchangesoftheheadandbodypositionnoother
neurologicaldeficitispresent.Somemedicationsmayalsocausevertigo.Dependingonthecauseofthevertigo,drugswithdifferentmechanismsofaction,
physicaltherapy,psychotherapy,aswellassurgerymaybeusedtocombatthisdisablingmalady.Symptomatictreatmenthasaparticularlyimportantrole,
regardlessoftheetiologyofvertigo.Wereviewedthecurrentmedicationsrecommendedforpatientswithvertigo,theirmechanismsofactionandtheirmost
frequentsideeffects.

Howtocitethisarticle:
BerisavacII,PavloviAM,TrajkoviJJ,terniNM,BumbaireviLG.Drugtreatmentofvertigoinneurologicaldisorders.NeurolIndia201563:933939

HowtocitethisURL:
BerisavacII,PavloviAM,TrajkoviJJ,terniNM,BumbaireviLG.Drugtreatmentofvertigoinneurologicaldisorders.NeurolIndia[serialonline]2015[cited2017May7
]63:933939
Availablefrom:http://www.neurologyindia.com/text.asp?2015/63/6/933/170097

FullText

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5/7/2017 Drugtreatmentofvertigoinneurologicaldisorders:<b>IvanaIBerisavac,AleksandraMPavlovi,JasnaJ.ZidvercTrajkovi,NadedaM.ovikoviterni,LjiljanaG.BeslaBumbairevi</b>,Neurololy

Introduction

Vertigoisacommonsymptomthatmaybeamanifestationofseveralunderlyingetiologiesandmaybecausedbydamagewithintheinnerear,byafflictionsof
thebrainstemandcerebellum,ormayevenbepsychogenicinorigin.[1],[2]Afterheadache,vertigoisthesecondmostcommonsymptomencounteredin
patientsinneurologicaloutpatientfacilitiesaroundtheworld.[1]

Anacuteonsetvertigowithnauseaandvomitingusuallyreflectsdamagetothevestibularsystem.Vertigoitselfmayeitherbeofperipheralorcentraltype.[2]
Themostfrequentcausesincludevestibularneuritis,labyrinthitis,multiplesclerosis,orstrokeintheregionofthebrainstemorcerebellum.[3]Centraltype
vertigoiscausedbylesionsofthecentralnervoussystem,andisoftenassociatedwithfocalneurologicaldeficitssuchashemiparesis,hemisensoryloss,speech
disturbance,ataxia,orgazepalsy.[3],[4]Acutespontaneousvertigothatisassociatedwithlossofbalance,isaccompaniedbyasenseofrotationofthe
surroundingsorself,isworsenedwiththechangingpositionoftheheadandbody,withtheabsenceofassociatedneurologicaldeficits,isthemain
manifestationofperipheralvertigo,thatoccursasaconsequenceoflesionsoftheperipheralvestibularsystem.[5]Asmanyas93%ofpatientswithvertigo
seenbyaprimarycarephysiciansufferfrombenignparoxysmalpositionalvertigo(BPPV),acutevestibularneuritis,orMnire'sdisease.Thedifferencesinthe
clinicalpresentationofbothsyndromesareshownin[Table1].Theuseofmedicationssuchasaselectgroupofanticonvulsants,antidepressants,
antihypertensives,diuretics,andbarbituratescanalsocausevertigo[6]Vestibulardisorderscanbetreated,dependingontheiretiology,withmedications,
physicaltherapy,psychotherapy,orbysurgicalintervention.[2],[7]{Table1}

TreatmentofPeripheralVertigo

Benignparoxysmalpositionalvertigo

Thebenignparoxysmalpositionalvertigo(BPPV)occurssecondarytoaccumulationofcalciuminthesemicircularcanals(canalithiasis).[8],[9]Itischaracterized
byvertigoduringsuddenheadmovements,describedbythepatient,asthefeelingofrotationofthesurroundings.Itmostfrequentlydevelopsinthemorning,
withchangingpositionoftheheadwhilegettingoutofbed.Nauseaandsometimesvomitingaccompaniesitforafewsecondsupto1min.Occasionally,
patientsreportthefeelingoftransientinstabilityaftertheoccurrenceofvertigo.Examinationrevealsverticalrotatorynystagmus,directedupordown,more
pronouncedonthesideoftheaffectedear.TheDixHallpike'smaneuver,whichprovokesacharacteristicnystagmus,isusedtoconfirmthediagnosis.[10]

BPPVusuallyresolvesspontaneouslywithinafewweeks.ItisimportanttoadvisepatientswithBPPVtoslowlygetoutofbedandavoidactivitiesthatrequire
suddenmovementsoftheheadorlookingup.[11]Inpatientswithpronouncednauseaandvomiting,metoclopramide10mgcanberecommendedviaan
intramuscularinjection,intravenousbolusdoseorwithinanintravenousinfusionofnormalsaline.Thedrugcanberepeatedatevery68hduringthefirst3
days.Anotherantiemeticdrugthatmaybeadvisedispromethazine12.550mgevery46h.[12]Thisisaweakantipsychoticdrugbutapowerfulsedative
medicamentwithantiemeticandanticholinergiceffects.Themostcommonsideeffectsofthesedrugsareduetotheireffectondopaminereceptorsthatmay
precipitatetardivedyskinesiaandakathisiaor,theireffectoncholinergicreceptorsthatmaycauseadrymouth,irritability,disorientationandconstipation.
Epilepticseizuresandneurolepticmalignantsyndromeareextremelyraresideeffects.Theuseofpromethazineisnotrecommendedforchildrenyoungerthan
6yearsofageduetotheriskofrespiratorydepressionandsleepapnea,aswellasinelderlypatients,duetotheanticholinergiceffectsofthemedication.[13],
[14]

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SignificantreliefinthesymptomsprecipitatedbyBPPVisachievedbyapplyingtheEpleymaneuver,whichiseffectivein5090%ofpatients.[8],[10]Other
interventions,suchastheSemontmaneuverandpositioningtestforthehorizontalsemicircularcanalmayalsobeused.[1]Thesemaneuversshouldnotbe
appliedinpatientswithcoexistingdiseasesoftheneckandspine,significantcarotidarterystenosis,orsevereheartdiseases.[9],[11]Inpatients,inwhom
thesemaneuversarecontraindicated,rehabilitationshouldinitiallybecarriedoutunderthestrictsupervisionofaspecialist,Subsequently,thepatient'straining
intheuseofselfappliedexercises(BrandtDaroffexercises)isrecommended.[9]

Vestibularneuritis

Acuteonsetofvertigo,thatisdescribedbypatientsasanillusionofmovementorasenseofrotationofobjectssurroundingthepatientorthefeelingof
rotationofthepatienthimselfinspace,maybeduetovestibularneuritis(neuronitis,labyrinthitis,neurolabirintitisorunilateralvestibulopathy).[1]Theillness
usuallylastsforafewhours,daysorweeks,followedbypronouncednausea,vomitingandgaitinstability.Mostfrequently,thediseaseisassociatedwithherpes
simplexvirustype1whichaffectsthevestibularganglionandleadstolossoffunctionofthevestibularlabyrinth.[5]

Neurologicalexaminationrevealshorizontalnystagmuswitharotatorycomponent,morepronouncedonthesideoftheintactvestibularnerve.The
neurologicalexaminationisnormal.Romberg'stestispositive,andthepatientfallstothesideofthelesion.[5],[15]Usefultestsforthequickdiagnosisofthis
diseaseareheadshakingtest,whichdirectstheslowphaseofthenystagmustothedamagedearanditsquickphasetotheundamagedear.[16]TheHead
ImpulseThrustTestshowsthatrapideyefixationmovementsarelostonthesideofthedamagedearwhilesaccadesmaybeseen.[15]

Inadditiontotheusuallyoccurringunilateraldamagethatproducestheabovementionedmanifestations,bilateraldamagetothevestibularnervemayalso
occur,andisusuallysecondarytotheeffectofototoxicdrugssuchasgentamicin.Bilateraldamagemayalsobeseenincerebellardegeneration,meningitis,
autoimmunedisease,neuropathies,tumors,vestibularneuritis,andvariousotologicdiseases.[17]

Treatmentofvestibularneuritiscanbesymptomaticandspecific.Thesymptomatictherapyisdirectedtowardsthetreatmentofvertigo,nausea,andvomiting
duringthefirst3days,whenthesymptomsaremostpronounced.Withseverevomiting,parenteraltherapymayneedtobeinstituted[Table2].{Table2}

Antihistaminicdrugsarepreferredastheyhavesedativeeffects,aswellasagonisticorantagonisticeffectsonH1,H2,H3receptors,andactonthecentral
componentsofthevestibularsystem.[13]Therecommendeddosageofchloropyramineis20mg.Thismedicationmayberepeated23timesaday.
Promethazine25mgmaybeadministeredintramuscularlyevery6hormaybegivenorallyastabletsorsyrup.[12]Meclizinetabletsof50mgcanbetaken
beforethestartofnausea,typicallyearlyinthemorning,inonetotwodosesperday,andthedosecanberepeatedat6hintervals.[18]Themostimportant
sideeffectofthisclassofdrugsissedationwhichismostsignificantwithpromethazine.Patientsshould,therefore,bewarnedtoavoidcomplexactivitiessuch
asdrivingamotorvehiclewhiletakingthismedication.[19]

Anticholinergicsactingonmuscarinicreceptorssuchasscopolamineincreasethepatient'stolerancetomovementandthus,playanimportantroleinthe
treatmentofvertigo.[13]Dueofthiseffect,(theyareoftenusedtotreatmotionsickness(includingseasickness,whentheymaybeappliedintheformof
patchesfixedovertheear.Theyareoftenusedbydiversalsointhisform.Thesideeffectsarerare,occurringin<1%ofpatientsandarecausedby
anticholinergiceffectsofthemedication.Theseincludedrymouth,mydriasis,sweatingdisorder,tachycardiafollowedbybradycardia,urinaryretention,and
constipation.[14]Elderlypatientsmaydevelopdisorientation,confusion,andandevenanhallucinatorysyndromewithagitation.Thesedrugscanprovoke
seizuresandarecontraindicatedinpatientswithepilepsy.Hypersensitivityreactionsarepossible.[20]Theiruseiscontraindicatedinseverekidneyorliver
disease,prostatichypertrophy,ileus,urinaryretention,heartarrhythmia,andglaucoma.Theiruseisnotrecommendedduringpregnancyandlactation.[19]

Benzodiazepines,inadditiontotheirsedativeeffect,alsoinhibitthevestibularresponsebypotentiatingtheactionofgammaaminobutyricacid.The
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recommendedmedicationsofthisgrouparediazepam10mgparenterallyororally,whichmayberepeatedevery6h,lorazepam1mgintravenousor2.5mg
astheoraldose,orclonazepam0.5mgintravenousor2mgintheformoftablets.Theoralformsofthesedrugsmaybegiveninpatientswithlesspronounced
vomiting.Theseareusuallyadministered23times/daywithagradualincreaseoftheirdose.[14],[20]Duetotheirsedativeeffect,cautionisneededinthe
elderlypopulation.Withintravenousadministration,hypotensionandrespiratorydepressionmayoccur.[14],[19],[20]

Incasesofvestibularnerveneuritis,vitaminBisoftenadministeredsinceVitaminBdeficiencymayleadtooccurrenceofnauseaandvomiting(specificallydue
tovitaminB6deficiency)andringingintheear(specificallyduetovitaminB3,B6,andB12deficiency).VitaminBcomplexmaybegivenorallyorasan
intravenousinfusion(thelatterincaseswithfrequentvomiting)andmayberepeated23timesaday.Theyhavenoothershorttermadverseeffectswiththe
exceptionofanoccasionalhypersensitivityreaction.[21][Table3]showsthespecifictreatmentoptionstobeusedincasessufferingfromvestibularneuritis.
{Table3}

Corticosteroidshaveanantiinflammatoryandantiedemaeffect.Theuseofmethylprednisolone100mgdailyinanintravenousinfusionisrecommended
duringthefirst3daysofillness,withitsdosetaperingevery3rddayby20mguntilthedrugisstopped.[22]Prednisonemayalsobegiveneitherorallyoras
combinedintravenousandoraltherapy.Corticosteroidsshouldalwaysbeusedwithgastroprotectivedrugsandthepatientspotassiumlevelsshouldbe
constantlymonitored.Steroidsarecontraindicatedinpatientssufferingfromuncontrolledhypertensionordiabetesmellitus,pepticulcer,osteoporosis,
infections,tuberculosisandhepaticdysfunction.[22],[23]

BetahistineactsasanH1receptoragonist(increasingthecochlearandcerebralcirculation)aswellasanH3receptorantagonist(inhibitingthereleaseof
histamineandtherefore,suppressingthefunctionofthevestibularnuclei).Itmaybegivenorally,23timesdailyanditsdosehastobetitratedaccordingto
anindividualpatient.Itismoreeffectiveathigherdoses.[24]Themostcommonsideeffectsareheadacheandgastricdisorders,andthedrugiscontraindicated
inpatientswithapheochromocytoma.Hypersensitivityreactionsarealsodescribed.Itsadministrationhastocarefullymonitoredifthepatienthasbronchial
asthma.Itisnotrecommendedforuseinpregnancyandinlactatingmothers,orinchildren.[25],[26]

Calciumchannelblockerssuchasflunarizine5mgorallyadministeredonceaday,orcinnarizine75mgorallyadministered23times/day,arerecommended
whenantihistaminesandantiemeticshavehadnoeffect.Theeffectofsuppressionofthevestibularresponsesisachievedusingthesedrugsforalongerperiod
of68weeks.[20]Themostcommonsideeffectsofthisclassofdrugsaredrowsiness(whichendangerstheperformanceofcomplexmotortaskssuchas
drivingacar)andalsoweightgain.Gastricdisturbancesanddepressionarelesscommon.Thesedrugsarenotrecommendedduringpregnancy.[19]

Inadditiontothepharmacologicaltreatment,psychotherapyandphysicaltherapymayalsobeusedinthetreatmentofchronicvertigo.[27]

Mnire'sdisease

Thisisachronicdiseasecharacterizedbyintermittentepisodesofvertigothatlastforminutesorhours,andisassociatedwithtinnitusandhearingloss.The
diseasecanprogresstodeafnessduetodisordersofmicrocirculationinthelabyrinth.[28]ItisassumedthatthecauseofMnire'sdiseaseisendolymphatic
hydrops,butthepathogenesisisusuallymultifactorial,withtheparticipationofimmunological,metabolic,viral,traumatic,andallergicfactors.Apatient's
geneticpredispositionmayalsoplayarole.Itcanoccuratanyagebutusuallymanifestsbetween40and60yearsofage,andoccursmorefrequentlyin
women.[28]Thediagnosisisbasedonhistory,clinicalpresentation,neurologicalexamination,andaudiologicaltests.Attheonsetofthedisease,the
examinationandinvestigationtypicallyshowhearinglossatlowfrequencies,andinthefurthercoursealsoatthehighfrequencies.[28]Thesamedrugsused
forthetreatmentofvestibularneuritisareadministered[Table2]and[Table3].Inaddition,betablockersandthiazidediuretics(toreducefluidfromthe
damagedear)maybegiven.InMeniere'sdisease,vasodilatorssuchasbetahistineareusedinmuchlargerdosesofupto192mg/day,andoveralongerperiod
oftimethatmayextendtoevenayear.[29]Betahistinetakenorallyreleaseshistamine,increasescochlearflow,andcausesvasodilationinthestriavascularis,
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allofwhichhelpinreducingendolymphaticpressure.[26],[30]Whenmedicaltherapyhasnoeffect,surgicaltreatmentshouldbeconsidered.Patientsare
recommendedbedrestandtoldtoavoidmovements.Theyarealsoaskedtostoptheiralcoholandtobaccousage,andtobringaboutamodificationintheirdiet
(toavoidsaltinordertoreducebody'sfluidretention).[31]

Phobicposturalvertigo

Theunderlyingpathologicalprocessesinthisconditionaredifferentmentaldisorders,depression,andanxiety.Accordingtosomedata,phobicposturalvertigois
thesecondmostcommondiagnosisinapatientwithvertigo.[32]Patientsoftencomplainofposturalvertigo,whichtheydescribeasdizzinessandpostural
sway,driftorgaitinstability.Allofthesemanifestationsincreaseordecreaseindifferentprovocativesituations.Theaffectedpersonsoftenfall,andthis
symptomisusuallymanifestedinfrontofotherpeople.Apatientwithanobsessivecompulsivepersonalityandatendencytowardsintrospection,ora
depressedpatient,ispronetothiscondition.[32]Neurologicalexaminationisalwaysnormal.In25%ofpatientswithphobicvertigo,awelldefinedvestibular
disorderactuallyprecedesthiscondition.[32]

Afterdetaileddiagnostictestshaveruledoutothercausesofvertigo,physiciansshouldexplaintothepatientthatnoorganicdiseasehasbeenfound
treatmentisthendirectedataddressingthepatient'sfear.Psychoeducationaltherapyandaninterviewwithapsychologistorpsychiatristusuallyleadstogood
results.[33]Ifpharmacoherapyisneededfordepression,selectiveserotoninreuptakeinhibitorsarerecommended,whichareadministeredonceaday,inthe
morningTheseincludefluoxetine20mg,paroxetine10mg,sertraline50mgortricyclicantidepressants,suchasimipramine25mgdividedintothreedaily
dosesoramitriptyline10mg(atbedtime).Thesideeffectsofthisclassofdrugsareanxiety,insomnia,gastrointestinaldisturbances,decreasedlibido,and
sexualdysfunction.Theuseofparoxetineisnotrecommendedduringpregnancybecauseofitsteratogenicpotential.[19]Apotentiallylifethreatening
serotoninsyndrome,secondarytoexcessofserotonininthebodycanoccurwhilethisclassofdrugsisbeinggiven.Theriskisincreasedwhenanew
combinationofmedicationsisadministered,bothofwhichaffectserotoninlevels.Itmayalsooccurwhenthedosageofanexistingdrugaffectingserotonin
levelsisadditionallyincreased.Therefore,monoamineoxidaseinhibitorsortriptansshouldnotbeusedwithselectiveserotoninreuptakeinhibitors.Itis
advisabletoavoidfoodmaterialcontainingtyramine,forexample,agedcheeseorredwine.However,thesideeffectsarerareandsignificantlylesspronounced
thanencounteredwhentricyclicantidepressantsareused.Tricyclicantidepressantsmaycausedrowsinessorinsomnia,tremors,antimuscariniceffectssuchas
blurredvision,constipationandurinaryretention,hypotensionandcardiacarrhythmia,disorientation,andseizures.Thesemedicationsoftenleadtoweight
gainandsexualdysfunction.[14]Tricyclicantidepressanttherapyshouldbestartedinalowdose,especiallyinelderlypatients,andthedosesshouldbestepped
upgradually.[14],[19]

Forthetreatmentofanxiety,benzodiazepinesarerecommended.Theseincludediazepam,bromazepamandlorazepamadministeredorallyinlowdoses2to3
timesaday[Table4].[19],[20]{Table4}

TreatmentofVertigoandInstabilityCausedbyDiseasesoftheCentralNervousSystem

Themostcommoncausesofcentralvertigoarestrokeintheregionofthebrainstemorcerebellum,migraine,multiplesclerosis,andvestibularnervetumors.
[34],[35],[36]Vertigohasbeenreportedwithintheclinicalspectrumofmigraineattackandistreatedaccordingtothestandardprinciplesoftreatmentofan
acutemigrainousattack.Itcanalsooccurasasideeffectofdrugsadministeredforthemanagementofacutemigraine.Thesedrugsincludetriptans,aswellas
drugsusedintheprophylactictherapyofmigraine,suchasbetablockersorcalciumchannelblockers.[2],[37]Thetreatmentdependsontheunderlying
disease[Table5].{Table5}

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Inthecaseofstroke,standardacutestrokemanagementwithmeasuresforthesecondarypreventionofstrokeareinstituted.[4]Ifvertigooccursasa
symptomofastroke,othersymptomaticdrugswithdifferngmechanismsofactioncouldbeused[Table2]and[Table3].Inthecaseofmultiplesclerosis,
standardtherapeuticprinciplesareapplied.[14]Besidesvestibularnervetumors,vertigocanalsobeduetoarachnoidalcystsintheposteriorfossaorArnold
Chiarimalformationinthesecases,besidessymptomatictherapy,surgicalinterventionmayalsobeconsidered.Inrarecasesofepisodicataxiatype2,caused
byanautosomaldominantmutationintheCACNA1Ageneresultinginthedysfunctionofvoltagedependentcalciumchannels,theuseof4aminopyridine
(potassiumchannelblocker)andacetazolamideisrecommended.[38]Thesideeffectsofboththesedrugsaredistalparesthesiasaminopyridinecanpredispose
toepilepticseizuresandarrhythmia,whileacetazolamidecanbeassociatedwithchangesintasteaswellasnausea,vomiting,diarrhea,polyuria,and
drowsinessorconfusion(thelatterdueduetodehydration).Theuseofacetazolamidemayprecipitatethedevelopmentofrenalcalculisopatientsshouldbe
advisedtodrinkplentyoffluidswhilebeingonthismedication.[38],[39]

Forpatientswithcentralvertigoofvascularetiology,especiallyinthegeriatricpopulation,theuseofnicergoline,aderivativeofergotalkaloidscanbe
recommended.[40]Thisdrugisapotent,selectiveantagonistofthealpha1Aadrenergicreceptorswithaprimaryeffectofraisingbloodflowbyitsvasodilatory
mechanism.[41]Thedrugalsoinhibitsplateletaggregation,increasesthecholinergicandcatecholaminergictransmissionandhasneurotrophicandantioxidant
properties.[42]Therecommendeddosesare510mg,3timesaday.Thesideeffectsincludenausea,hotflushes,mildgastricdisturbances,andhypotension.
Highdosesofthedrugcancausebradycardia,increasedappetite,agitation,diarrhea,andsweating.Thedrugisnotrecommendedduringpregnancy.Itisalso
contraindicatedinporphyria.Rarebutimportantcomplicationsofergotderivativesarefibrosisandergotism.Itisnecessarytoavoiditsconcomitantusewith
propranololwhosecardiodepressiveeffectsarepotentiated.Cautionisalsoneededifthisdrugiscombinedwithothervasodilators.[14],[42]

Forpatientswithchronicvertigo,vestibularrehabilitationisalsorecommended.[27]

Conclusion

Vertigoisacommoncomplaintineverydayclinicalpractice.Thecausesofvertigoarenumerousandtreatmentdependsontheunderlyingetiology.Drugswith
differentmechanismsofaction,physicaltherapy,psychotherapy,andinsomecases,surgicalinterventionmaybeadministered.Symptomatictreatmenthasa
specialroleintheameliorationofvertigoregardlessofitsetiology.Whileadministeringmedicationsforthetreatmentofvertigo,itisimportanttounderstand
theirmechanismsofactionandsideeffects.

Acknowledgment

ThisworkwassupportedbytheprojectoftheMinistryofScienceofSerbiaNo.175022.

Financialsupportandsponsorship

ThisworkwassupportedbytheprojectoftheMinistryofScienceofSerbia.

Conflictsofinterest

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5/7/2017 Drugtreatmentofvertigoinneurologicaldisorders:<b>IvanaIBerisavac,AleksandraMPavlovi,JasnaJ.ZidvercTrajkovi,NadedaM.ovikoviterni,LjiljanaG.BeslaBumbairevi</b>,Neurololy

Therearenoconflictsofinterest.

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