FrancophonIA/ELRC3.0 huggingface dataset:
English: • swelling, including swelling of hands, ankles or feet (peripheral oedema)
Danish: • hævede hænder, ankler eller fødder (perifere ødemer)
English: 98 tablets (2x49, PA/Alu/PVC blisters) 98 tablets (2x49x1, PVC/PCTFE single-unit-dose blisters) 280 tablets (20x14, PVC/PCTFE blisters) 280 tablets (20x14, PA/Alu/PVC blisters)
Danish: 98 tabletter (2x49, PA/Alu/PVC blister) 98 tabletter (2x49x1, PVC/PCTFE enkeltdosisblister) 280 tabletter (20x14, PVC/PCTFE blister) 280 tabletter (20x14, PA/Alu/PVC blister)
English: The fertility of rats was unaffected at doses of up to aliskiren 250 mg/kg/day (see section 5.3).
Danish: Rotters fertilitet var upåvirket ved doser op til 250 mg/kg/dag (se pkt.
English: Safety data for amlodipine are well established both clinically and non-clinically.
Danish: Både kliniske og ikke-kliniske sikkerhedsdata for amlodipin er veletableret.
English: ***Including one case of “liver failure fulminant” reported in the post-marketing experience, for which a causal relationship with aliskiren cannot be excluded.
Danish: ***Inklusive et tilfælde af 'fulminant leversvigt', der er rapporteret post-marketing, og hvor en kausal
English: Liver disorder a,
Danish: Leverforstyrrelser a,
English: Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients.
Danish: Amlodipins clearance har tendens til at være nedsat hos ældre patienter, resulterende i øget AUC og eliminationshalveringstid.
English: Calcium channel blockers act to prevent the influx of calcium into the vascular smooth muscle cells in the vessel wall, thereby preventing smooth muscle cell contraction and vasoconstriction.
Danish: Calciumantagonister virker ved at hindre indtrængning af calcium ind i karvæggens vaskulære glatte muskelceller, og forhindrer derved glatte muskelcellers sammentrækning og vasokonstriktion.
English: Mutagenicity studies revealed no effects related to the medicinal product at either the gene or
Danish: Mutagenicitetsstudier viste ingen lægemiddelrelaterede virkninger på hverken gen- eller kromosomniveau.
English: As for other medicinal products acting on the renin-angiotensin-aldosterone system, caution should be exercised when Rasilamlo is given in the presence of conditions pre-disposing to kidney dysfunction such as hypovolaemia (e.g. due to blood loss, severe or prolonged diarrhoea, prolonged vomiting, etc.), heart disease, liver disease, diabetes mellitus or kidney disease.
Danish: Som for andre lægemidler, der virker på renin-angiotensin-aldosteron-systemet, skal der udvises forsigtighed, når Rasilamlo gives til patienter, der er prædisponerede for renal dysfunktion som hypovolæmi (fx pga. blodtab, alvorlig eller vedvarende diarré, vedvarende opkastning), hjertelidelse, leverlidelse, diabetes mellitus eller nyrelidelse.
English: Therefore, in view of available data regarding aliskiren/ aliskiren,amlodipine / aliskiren, hydrochlorothiazide, the PRAC considered that changes to the product information were warranted.
Danish: Set i lyset af de tilgængelige data vedrørende aliskiren / aliskiren, amlodipin / aliskiren, hydrochlorthiazid, anser PRAC det for ønskeligt med en ændring af produktinformationen.
English: A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Rasilamlo therapy taking into account the benefit of breast-feeding for the child and the benefit of
Danish: Det skal besluttes, om amning eller behandling med Rasilamlo skal ophøre, idet der tages højde for fordelene ved amning for barnet i forhold til de terapeutiske fordele for moderen.
English: Dose should be individualised and adjusted according to the patient's clinical response.
Danish: Dosis bør individualiseres og skal justeres i
English: A number of these patients had a history of angioedema or symptoms suggestive of angioedema which in some cases was associated with the administration of other medicinal products known to cause angioedema, including RAAS blockers (ACEIs or ARBs).
Danish: En del af disse patienter havde en anamnese med angioødem eller symptomer, der tydede på angioødem, som i nogle tilfælde havde efterfulgt brug af andre lægemidler, der er kendt for at forårsage angioødem, inklusive RAAS-blokkere (ACEhæmmere eller ARB'er).
English: No adjustment of the initial dose is required for patients with mild to moderate renal impairment (GFR 89-60 ml/min/1.73 m and 59-30 ml/min/1.73 m 2, respectively, see sections 4.4 and 5.2).
Danish: Der kræves ingen justering af initialdosis for patienter med let til moderat nedsat nyrefunktion (GFR på henholdsvis 89-60 ml/min/1,73 m og 59-30 ml/min/1,73 m 2, se pkt.
English: Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of
Danish: Grundet risiko for hyperkaliæmi anbefales det, at samtidig indgift af calciumantagonister, såsom amlodipin, undgås hos patienter mistænkt for eller i behandling
English: Symptomatic hypotension could occur after initiation of treatment with Rasilamlo in the following
Danish: Symptomatisk hypotension kan forekomme hos patienter i behandling med Rasilamlo i følgende
English: The adverse reactions previously reported with one or both of the two active substances (aliskiren and amlodipine) of Rasilamlo and listed below may occur with
Danish: Bivirkninger, der tidligere er indberettet for et af eller begge de aktive stoffer (aliskiren og amlodipin) i Rasilamlo og er anført herunder, kan forekomme ved brug af
English: PERFORATED UNIT DOSE BLISTER (PCTFE)
Danish: PERFOREREDE ENKELTDOSISBLISTER (PCTFE)
English: The adverse reactions previously reported with one of the individual components of Rasilamlo (aliskiren and amlodipine) and included in the tabulated list of adverse reactions may occur with Rasilamlo.
Danish: Bivirkninger, der tidligere er indberettet for en af de individuelle komponenter i Rasilamlo (aliskiren og amlodipin) og inkluderet i tabellen over bivirkninger, kan forekomme med Rasilamlo.
English: In the event of any signs suggesting a hypersensitivity reaction/angioedema (in particular difficulties in breathing or swallowing, rash, itching, hives or swelling of the face, extremities, eyes, lips and/or tongue, dizziness) patients should discontinue treatment and contact the physician (see section 4.4).
Danish: Ved tegn tydende på en overfølsomhedsreaktion/angioødem (specielt besvær med vejrtrækning eller synkning, udslæt, kløe, urticaria eller hævelse i ansigt, ekstremiteter, øjne, læber og/eller tunge, svimmelhed), skal patienten afbryde behandlingen og kontakte lægen (se pkt.
English: Following intravenous administration, mean plasma
Danish: Efter intravenøs administration er den gennemsnitlige
English: Dual blockade of the RAAS with aliskiren, ARBs or ACEIs Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACEIs, ARBs or aliskiren is associated with a higher frequency of adverse events such as hypotension, stroke, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Danish: Dobbelt RAAS-blokade med aliskiren, ARB'er eller ACE-hæmmere Data fra kliniske studier har vist, at dobbelthæmning af RAAS ved kombinationsbehandling med ACE-hæmmere, ARB'er eller aliskiren er forbundet med en højere hyppighed af bivirkninger som hypotension, apopleksi, hyperkaliæmi og nedsat nyrefunktion (inklusive akut nyresvigt) sammenlignet med brug af et enkelt RAAS-virkende lægemiddel (se pkt.
English: Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Hypotension, syncope, stroke, hyperkalaemia, and decreased renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system (see section 5.1).
Danish: Dobbelt hæmning af renin-angiotensin-aldosteronsystemet (RAAS) Der er rapporteret hypotension, synkope, apopleksi, hyperkaliæmi og nedsat nyrefunktionen (herunder akut nyresvigt) hos følsomme patienter, specielt ved anvendelse af flere lægemidler, der påvirker dette system (se pkt.
English: Rare (may affect up to 1 in 1,000 people):
Danish: Sjælden (kan forekomme hos op til 1 ud af 1.000 patienter):
English: Rasilamlo is indicated for the treatment of essential hypertension in adult patients whose blood pressure is not adequately controlled with aliskiren or amlodipine used alone.
Danish: Rasilamlo er indiceret til behandling af essentiel hypertension hos voksne patienter, hvis blodtryk ikke er tilstrækkeligt kontrolleret med aliskiren eller amlodipin anvendt alene.
English: Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.
Danish: Reproduktionsstudier med rotter og mus har vist forsinket fødsel, forlænget fødsel og nedsat overlevelse af afkommet ved doser ca. 50 gange højere end de maksimalt anbefalede doser til
English: The results showed that developmental changes of aliskiren exposure correlated with the ontogeny of transporter maturation in jejunum, liver, kidney and brain.
Danish: Resultaterne viste, at udviklingsmæssige ændringer i aliskiren-eksponeringen korrelerede med ontogenesen af transportermodning i jejunum,
English: Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, renin inhibitors, ATC
Danish: Farmakoterapeutisk klassifikation: Stoffer, der virker på renin-angiotensin-systemet, reninhæmmere,
English: , hepatic enzymes increased (mostly consistent with cholestasis)
Danish: , forhøjede leverenzymer (mest i forbindelse med kolestase)
English: Hypersensitivity to the active substances or to any of the excipients listed in section 6.1, or
Danish: Overfølsomhed over for de aktive stoffer eller over for et eller flere af hjælpestofferne anført i
English: In hypertensive patients not controlled by the component monotherapies, once-daily administration of Rasilamlo provided dose-dependent clinically meaningful reductions in both systolic and diastolic
Danish: Hos hypertensive patienter, som ikke var kontrolleret på behandling med de aktive stoffer som enkeltstofbehandling, gav administration af Rasilamlo en gang dagligt dosisafhængig klinisk relevant reduktion i både systolisk og diastolisk blodtryk.
English: In hypertensive patients, once-daily administration of aliskiren at doses of 150 mg and 300 mg provided dose-dependent reductions in both systolic and diastolic blood pressure that were maintained over the entire 24-hour dose interval (maintaining benefit in the early morning) with a mean peak to trough ratio for diastolic response of up to 98% for the 300 mg dose.
Danish: Hos hypertensive patienter gav administration af aliskiren en gang dagligt i doser på 150 mg og 300 mg dosisafhængige reduktioner i både det systoliske og det diastoliske blodtryk, som blev opretholdt over hele dosisintervallet på 24 timer (med vedvarende gavnlig virkning tidligt om morgenen) med en gennemsnitlig peak/trough ratio for diastolisk respons på op til 98 % for 300-mgdosen.
English: In a study in 545 randomised patients not adequately responsive to 5 mg amlodipine, the combination of aliskiren 150 mg/amlodipine 5 mg resulted in greater blood pressure reduction than those patients
Danish: I et studie med 545 randomiserede patienter, der ikke responderede tilstrækkeligt på behandling med amlodipin 5 mg, viste kombinationen af aliskiren/amlodipin 150 mg/5 mg en større blodtryksreduktion, end for de patienter der fortsat fik amlodipin 5 mg.
English: Experimental data suggest that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites.
Danish: Data fra dyrestudier tyder på, at amlodipin binder til både dihydropyridin og ikke
English: No long-term efficacy data for aliskiren in patients with heart failure are currently available.
Danish: Der foreligger i øjeblikket ingen langtidsdata for effekten af aliskiren hos patienter med
English: Combination therapy studies are available for aliskiren added to the diuretic hydrochlorothiazide and the beta blocker atenolol.
Danish: Der er undersøgelser af kombinationsbehandling tilgængelige, hvor aliskiren er kombineret med diuretikummet hydrochlorthiazid og betablokkeren atenolol.
English: In clinical studies in hypertensive patients, aliskiren had no clinically important effects on total cholesterol, high density lipoprotein cholesterol (HDL-C), fasting triglycerides, fasting glucose or uric acid.
Danish: I kliniske studier af hypertensive patienter havde aliskiren ingen klinisk signifikant virkning på total kolesterol, HDL-kolesterol, fastende triglycerider,
English: Angioedema a, erythema a
Danish: Angioødem a, erytem a
English: Delayed mortality was observed at 300 mg/kg/day (8.5-fold the MRHD on mg/m2 basis assuming a 60 kg adult patient) with no cause of death
Danish: Der blev observeret forsinket mortalitet ved 300 mg/kg/dag (8,5 gange MRHD baseret på mg/m antaget for en voksen patient på 60 kg), uden at
English: Aliskiren was evaluated for cardiovascular and/or renal benefit in a double-blind placebo controlled randomised trial in 8,606 patients with type 2 diabetes and chronic kidney disease (evidenced by proteinuria and/or GFR <60 ml/min/1.73 m2) with or without cardiovascular disease.
Danish: Aliskirens eventuelle gavnlige virkning på hjerte-kar og/eller nyrer blev undersøgt i et dobbeltblindt, placebokontrolleret, randomiseret studie hos 8.606 patienter med type 2-diabetes og kronisk nyresygdom (vist ved proteinuri og/eller GFR < 60 ml/min/1,73m2) med eller uden hjerte-karsygdom.
English: Hyperkalaemia a
Danish: Hyperkaliæmi a
English: Rifampicin, which is an inducer of P-gp, reduced aliskiren bioavailability by approximately 50% in a clinical study.
Danish: Rifampicin, som er en P-gpinduktor, nedsatte aliskirens biotilgængelighed med omkring 50 % i et klinisk studie Andre induktorer af P-gp (prikbladet perikum) kan muligvis nedsætte aliskirens biotilgængelighed.
English: Common (may affect up to 1 in 10 people):
Danish: Almindelig (kan forekomme hos op til 1 ud af 10 patienter):
English: Amlodipine causes blood vessels to dilate and relax, thus blood pressure
Danish: Amlodipin får blodkarrene til at udvide sig og slappe af, og derved
English: Another repeat-dose toxicity study was conducted in juvenile rats 14 days post-partum for 8 weeks with aliskiren dosing at 30, 100 or 300 mg/kg/day.
Danish: Et andet toksicitetsstudie med gentagne doser blev udført på unge rotter 14 dage post-partum i 8 uger med aliskiren-doser på 30, 100 eller 300 mg/kg/dag.
English: Hyponatraemia a
Danish: Hyponatriæmi a
English: It is also available in multi-packs of 98 tablets (2 packs of 49) and 280 tablets (20 packs of 14) in calendar blisters and 98x1 tablet (2 packs of 49x1) as perforated unit dose blisters.
Danish: Det er også tilgængeligt i multipakninger på 98 tabletter (2 pakninger af 49) og 280 tabletter (20 pakninger af 14) i kalenderpakninger og 98x1 tabletter (2 pakninger af 49x1) som perforerede
English: • allergic reactions (hypersensitivity) and angioedema (the symptoms of which can include difficulties in breathing or swallowing, rash, itching, hives or swelling of the face, hands and feet, eyes, lips and/or tongue, dizziness)
Danish: • overfølsomhedsreaktioner (allergiske reaktioner) og angioødem (symptomerne kan være besvær med at trække vejret eller med at synke, udslæt, kløe, nældefeber eller hævet ansigt, hænder og fødder, øjenomgivelser, læber og/eller tunge, svimmelhed)
English: Aliskiren is not recommended in patients with severe renal impairment (glomerular filtration rate (GFR) <30 ml/min/1.73 m
Danish: Aliskiren anbefales ikke til patienter med stærkt nedsat nyrefunktion (glomerulær filtrationsrate (GFR) < 30 ml/min/1,73 m
English: Adverse reaction observed with monotherapy with amlodipine; * Peripheral oedema is a known, dose-dependent adverse reaction of amlodipine and has also been reported with aliskiren therapy in post-marketing experience.
Danish: Bivirkning observeret ved monoterapi med aliskiren Bivirkning observeret ved monoterapi med amlodipin *Perifert ødem er en kendt, dosisafhængig bivirkning ved amlodipin, og er også indberettet ved behandling med aliskiren efter markedsføring.
English: A number of these patients had a history of angioedema or symptoms suggestive of angioedema, which in some cases followed use of other medicinal products that can cause angioedema, including RAAS blockers (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) (see
Danish: Et antal af disse patienter havde en anamnese med angioødem eller symptomer, der tydede på angioødem, som i nogle tilfælde havde optrådt efter brug af anden medicin, der kan forårsage angioødem, inklusive RAAS-blokkere (angiotensin-konverteringsenzym-hæmmere eller angiotensin
English: • rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever
Danish: • udslæt, rød hud; blister omkring læber, øjne eller mund, hudafskalning, feber
English: A repeat-dose toxicity study was conducted in juvenile rats 8 days post-partum for 4 weeks with aliskiren dosing at 30, 100 or 300 mg/kg/day.
Danish: Et toksicitetsstudie med gentagne doser blev udført på unge rotter 8 dage post-partum i 4 uger med aliskiren-doser på 30, 100 eller 300 mg/kg/dag.
English: Rasilamlo 150 mg/5 mg film-coated tablets Rasilamlo 150 mg/10 mg film-coated tablets Rasilamlo 300 mg/5 mg film-coated tablets Rasilamlo 300 mg/10 mg film-coated tablets Aliskiren/amlodipine
Danish: Rasilamlo 150 mg/5 mg filmovertrukne tabletter Rasilamlo 150 mg/10 mg filmovertrukne tabletter Rasilamlo 300 mg/5 mg filmovertrukne tabletter Rasilamlo 300 mg/10 mg filmovertrukne tabletter Aliskiren/amlodipin
English: In an 8-week randomised, double-blind, placebo-controlled, parallel group factorial study in 1,688 randomised patients with mild to moderate hypertension, treatment with Rasilamlo at doses from 150 mg/5 mg to 300 mg/10 mg produced dose-dependent clinically meaningful mean blood pressure reductions (systolic/diastolic) ranging between 20.6/14.0 mmHg and 23.9/16.5 mmHg, respectively, compared to 15.4/10.2 mmHg for aliskiren 300 mg, 21.0/13.8 mmHg for amlodipine 10 mg and 6.8/5.4 mmHg with placebo in a population of patients with mean baseline blood pressure of 157.3/99.7 mmHg.
Danish: I et randomiseret, dobbelt-blindet, placebokontrolleret, parallelgruppe faktoriel studie af 8 ugers varighed med 1.688 randomiserede patienter med mild til moderat hypertension, gav behandling med Rasilamlo ved doser fra 150 mg/5 mg til 300 mg/10 mg dosisafhængige, klinisk meningsfulde blodtryksreduktioner (systolisk/diastolisk) på mellem henholdsvis 20,6/14,0 mmHg og 23,9/16,5 mmHg, sammenlignet med 15,4/10,2 mmHg for aliskiren 300 mg, 21,0/13,8 mmHg for amlodipin 10 mg og 6,8/5,4 mmHg med placebo, i en population af patienter med et gennemsnitligt blodtryk ved behandlingsstart (baseline-blodtryk) på 157,3/99,7 mmHg.
English: PVC/polychlorotrifluoroethylene (PCTFE) - Alu calendar blisters: Single pack containing 14, 28, 56, 98 tablets Multi-packs containing 280 tablets (20 packs of 14)
Danish: PVC/polychlortrifluorethylen (PCTFE) - Alu-kalenderblister: Enkeltpakninger indeholdende 14, 28, 56, 98 tabletter.
English: Caution should therefore be exercised when prescribing aliskiren to patients with a history of angioedema, and such patients should be closely monitored during treatment (see section 4.8) especially at the beginning of the treatment.
Danish: Der skal derfor udvises forsigtighed, når aliskiren ordineres til patienter med angioødem i anamnesen, og disse patienter skal følges tæt under behandlingen, især i
English: Liver enzyme increased a, weight increase weight decrease
Danish: Forhøjede leverenzymer a, vægtøgning vægttab
English: If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
Danish: Hvis dobbelthæmmende behandling anses for absolut nødvendig, bør dette kun ske under supervision af en speciallæge og under tæt monitorering af patientens
English: As with other medicinal products acting on the renin-angiotensinaldosterone system, angioedema or symptoms suggestive of angioedema (swelling of the face, lips, throat and/or tongue) have been reported in patients treated with aliskiren.
Danish: Som ved andre lægemidler, der virker på renin-angiotensin-aldosteron-systemet, er angioødem eller symptomer, som tyder på angioødem (hævet ansigt, læber, svælg og/eller tunge), blevet rapporteret
English: , altered bowel habits (including diarrhoea and constipation)
Danish: , ændrede afføringsvaner (inklusive diarré og forstoppelse)
English: Acute renal failure a, renal impairment a,
Danish: Akut nyresvigt a, nedsat nyrefunktion a,
English: Aliskiren was secreted in the milk of lactating rats.
Danish: Aliskiren udskilles i mælken
English: Uncommon (may affect up to 1 in 100 people):
Danish: Ikke almindelig (kan forekomme hos op til 1 ud af 100 patienter):
English: Rasilamlo was studied in a number of active and placebo-controlled trials and long-term trials which included a total of 5,570 hypertensive patients with mild to moderate hypertension (diastolic blood pressure between 90 mmHg and 109 mmHg).
Danish: Rasilamlo er undersøgt i et nogle aktiv- og placebokontrollerede studier og langtidsstudier, som samlet inkluderede 5.570 hypertensive patienter med mildt til moderat hypertension (diastolisk
English: Rasilamlo is not recommended in patients with severe renal impairment (GFR <30 ml/min/1.73 m
Danish: Rasilamlo anbefales ikke til patienter med stærkt nedsat nyrefunktion (GFR < 30 ml/min/1,73 m
English: For the surviving juvenile rats, no effects on behavioural or reproductive performance were observed.
Danish: Der blev ikke observeret nogen effekt på adfærd eller reproduktionsevne for de overlevende unge rotter.
English: , purpura
Danish: , alopeci purpura
English: Caution should be exercised when administering Rasilamlo to patients with hepatic impairment (see sections 4.2 and 5.2).
Danish: Der skal udvises forsigtighed, hvis Rasilamlo administreres til patienter med nesat leverfunktion (se pkt.
English: Caution required with concomitant use - P-gp interactions
Danish: Interaktioner med P-gp
English: The PRAC considered the cases of dechallenge and rechallenge to be important causal relationship information that contributes to
Danish: PRAC anså tilfældende med seponering og reeksponering for at være vigtige for vurderingen af kausal sammenhæng, da de
English: No adjustment of the initial dosage of aliskiren is required in patients with mild to moderate renal impairment (see sections 4.2 and 4.4).
Danish: Det er ikke nødvendigt at justere initialdosen af aliskiren hos patienter med let til moderat nedsat nyrefunktion (se pkt.
English: The concomitant use of Rasilamlo with an ACEI or an ARB is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m2) (see sections 4.5 and 5.1).
Danish: Samtidig brug af Rasilamo sammen med en ACE-hæmmer eller en ARB er kontraindiceret hos patienter med diabetes mellitus eller nedsat nyrefunktion (GFR < 60 ml/min/1,73 m2) (se
English: MDR1/Mdr1a/1b (P-gp) was found to be the major efflux system involved in intestinal absorption and biliary excretion of aliskiren in preclinical studies (see section 5.2).
Danish: I prækliniske studier er det vist, at MDR1/Mdr1a/1b (P-gp) er det vigtigste efflukssystem involveret i aliskirens intestinale absorption og biliære udskillelse (se pkt.
English: Children from birth to less than 2 years (see sections 4.2 and 5.3).
Danish: Børn fra fødslen og op til 2 år (se pkt.
English: , peripheral oedema c,a,am
Danish: , perifert ødem c,a,am
English: If any of the following occur, tell your
Danish: Hvis der opstår nyresvigt, skal
English: **, liver failure a,
Danish: **, leversvigt a,