FrancophonIA/ELRC3.0 huggingface dataset:
English: Do not take Skilarence - if you are allergic to dimethyl fumarate or any of the other ingredients of this medicine (listed in section 6) - if you have severe problems with your stomach or intestines - if you have severe liver or kidney problems - if you are pregnant or breast-feeding
Slovenian: Ne jemljite zdravila Skilarence - če ste alergični na dimetilfumarat ali katero koli sestavino tega zdravila (navedeno v poglavju 6); - če imate hude težave z želodcem ali prebavili;
English: The tablets are packed in PVC/PVDC-aluminium blisters.
Slovenian: Tablete so pakirane v pretisne omote iz PVC/PVDC-aluminija.
English: At week 16, patients treated with Skilarence had a lower mean DLQI compared to placebo (5.4 vs 8.8).
Slovenian: V 16. tednu so imeli bolniki, zdravljeni z zdravilom Skilarence, v primerjavi s placebom nižji povprečni DLQI (5,4 v primerjavi z 8,8).
English: Skilarence 30 mg is available in packs containing 42, 70 and 210 gastro-resistant tablets.
Slovenian: Zdravilo Skilarence 30 mg je na voljo v pakiranjih, ki vsebujejo 42, 70 in 210 gastrorezistentnih tablet.
English: Further studies have shown that dimethyl fumarate (and to a lesser extent monomethyl fumarate) reacts partially with reduced glutathione forming a glutathioneadduct.
Slovenian: Dodatne študije so pokazale, da dimetilfumarat (in v manjši meri monometilfumarat) deloma reagira z znižanim glutationom in tvori adukt glutationa.
English: Skilarence is a medicine that contains the active substance dimethyl fumarate.
Slovenian: Skilarence je zdravilo, ki vsebuje učinkovino dimetilfumarat.
English: - Pregnancy and breast-feeding.
Slovenian: − Nosečnost in dojenje.
English: Skilarence may reduce the number of your white blood cells.
Slovenian: Zdravilo Skilarence lahko zmanjša število belih krvničk pri vas.
English: The main activity of dimethyl fumarate and monomethyl fumarate is considered to be immunomodulatory, resulting in a shift in T helper cells (Th) from the Th1 and Th17 profile to a Th2 phenotype.
Slovenian: Glavna aktivnost dimetilfumarata in monometilfumarata naj bi bila imunomodulacijska, ki povzroča premik T-celic pomagalk (Th) s profila Th1 in Th17 v fenotip Th2.
English: For patients with pre-existing infections of clinical relevance, the physician should decide if treatment with Skilarence should only be initiated once the infection has resolved.
Slovenian: Pri bolnikih z obstoječimi klinično pomembnimi okužbami se mora zdravnik odločiti, ali se lahko zdravljenje z zdravilom Skilarence uvede šele, ko okužba mine.
English: If you have a serious infection, either before starting treatment with Skilarence or during treatment, your doctor may advise you not to take Skilarence until the infection has resolved.
Slovenian: Če imate resno okužbo, ki se pojavi pred uvedbo zdravljenja z zdravilom Skilarence ali med njim, vam bo zdravnik morda svetoval, da zdravila Skilarence ne jemljete, dokler okužba ne izzveni.
English: Your dose will be increased every week as shown in the table below (switching to 120 mg Skilarence tablets from week 4 onwards).
Slovenian: Vaš odmerek bo vsak teden povečal, kot je prikazano v spodnji preglednici (prehod na 120 mg tablete zdravila Skilarence od 4. tedna dalje).
English: 704 patients were randomised to receive Skilarence, an active comparator (Fumaderm, a combination product with the same content of dimethyl fumarate plus 3 monoethyl fumarate salts) and placebo in a ratio of 2:2:1.
Slovenian: 704 bolnikov je bilo randomiziranih za prejemanje zdravila Skilarence, aktivne primerjave (zdravilo Fumaderm, kombinirano zdravilo z enako vsebnostjo dimetilfumarata in s 3 monometilnimi fumaratnimi solmi) in placeba, v razmerju 2:2:1.
English: The inflammatory cytokine production is reduced with induction of proapoptotic events, inhibition of keratinocyte proliferation, reduced expression of adhesion molecules, and diminished inflammatory infiltrate within psoriatic plaques.
Slovenian: Nastajanje provnetnih citokinov se zmanjša z induciranjem proapoptotičnih dogodkov, inhibicijo proliferacije keratinocitov, zmanjšanim izražanjem adhezijskih molekul in zmanjšanim vnetnim infiltratom v psoriatičnih plakih.
English: In vitro studies have shown that hydrolysis of dimethyl fumarate to monomethyl fumarate occurs rapidly at pH 8 (pH in the small intestine), but not at pH 1 (pH in the stomach).
Slovenian: Študije in vitro so pokazale, da hidroliza dimetilfumarata v monometilfumarat hitro poteče pri pH 8 (pH v tankem črevesju), ne pa pri pH 1 (pH v želodcu).
English: Gastrointestinal tolerability can be improved by following the dose titration schedule on initiating Skilarence treatment and by taking Skilarence with food (see sections 4.2 and 4.8).
Slovenian: Prenašanje v prebavilih je mogoče izboljšati z upoštevanjem načrta za titracijo ob začetku zdravljenja z zdravilom Skilarence in z jemanjem zdravila Skilarence skupaj s hrano (glejte poglavji 4.2 in 4.8).
English: Diarrhoea was a common adverse reaction (36.9%) among patients taking Skilarence, leading to medicinal product withdrawal in about 10% of patients.
Slovenian: Diareja je bila pri bolnikih, ki so jemali zdravilo Skilarence, pogost neželeni učinek (36,9 %) in je povzročila opustitev jemanja zdravila pri približno 10 % bolnikov.
English: Avoid strong alcoholic drinks (more than 50 ml of spirits containing more than 30% alcohol by volume) during treatment with Skilarence, as alcohol can interact with this medicine.
Slovenian: Med zdravljenjem z zdravilom Skilarence se izogibajte uživanju močnih alkoholnih pijač (več kot 50 ml žgane pijače, ki vsebuje več kot 30 volumskih odstotkov alkohola), saj lahko alkohol medsebojno deluje s tem zdravilom.
English: There are no data available with Skilarence in paediatric patients.
Slovenian: Podatkov o uporabi zdravila Skilarence pri pediatričnih bolnikih ni na voljo.
English: If the side effects are not troublesome, your dose will be increased until your condition is well controlled.
Slovenian: Če neželeni učinki ne bodo povzročali težav, bo vaš odmerek povečeval, dokler vaša bolezen ne bo zadostno nadzorovana.
English: The coating of the gastro-resistant tablets is designed to prevent gastric irritation.
Slovenian: Obloga gastrorezistentnih tablet je zasnovana za preprečevanje draženja črevesja.
English: The objectives of the educational programme are to inform health care professionals about the risk of serious infections, mainly opportunistic infections such as progressive multifocal leukoencephalopathy (PML), and to provide guidance on the monitoring of lymphocyte and leukocyte count abnormalities.
Slovenian: Cilji izobraževalnega programa so obveščanje zdravstvenih delavcev o tveganjih resnih okužb, zlasti oportunističnih okužb, kot je progresivna multifokalna levkoencefalopatija (PML), in posredovanje smernic za spremljanje nenormalnih vrednosti limfocitov in levkocitov.
English: There was a trend in the efficacy endpoint PASI score mean % change from baseline, indicating the onset of a clinical response to Skilarence as early as week 3 (-11.8%) which became statistically significant compared to placebo by week 8 (-30.9%).
Slovenian: Opazili so trend v primarnem opazovanem dogodku učinkovitosti - spremembo povprečne ocene PASI v % od izhodišča, kar kaže na nastop kliničnega odziva na zdravilo Skilarence že v 3. tednu (-11,8 %), ki je do 8. tedna postal statistično pomemben v primerjavi s placebom (-30,9 %).
English: At week 16 of treatment, 13/175 (7.4%) of patients were noted to have lymphocyte levels <0.7x 10
Slovenian: V 16. tednu zdravljenja je bilo 13/175 (7,4 %) bolnikov obveščenih, da imajo ravni limfocitov < 0,7 x 10
English: Reproduction toxicity No fertility or pre- and post-natal development studies have been conducted with Skilarence.
Slovenian: Reproduktivna toksičnost Študij plodnosti ali predporodnega in poporodnega razvoja z zdravilom Skilarence niso izvedli.
English: Despite the high inter-subject variability, the exposure measured as AUC and Cmax was generally dose-proportional after single dose administration of 4 x 30 mg dimethyl fumarate tablets (total dose of 120 mg) and 2 x 120 mg dimethyl fumarate tablets (total dose of 240 mg).
Slovenian: Kljub veliki variabilnosti med preiskovanci je bila izpostavljenost, merjena kot AUC in Cmax na splošno sorazmerna z odmerkom po dajanju enkratnega odmerka 4 tablete po 30 mg dimetilfumarata (skupni odmerek 120 mg) in 2 tableti po 120 mg dimetilfumarata (skupni odmerek 240 mg).
English: A part of the total dimethyl fumarate is hydrolysed by esterases and the alkaline milieu of the small intestine, while the remainder enters the portal vein blood.
Slovenian: Del celokupnega dimetilfumarata se hidrolizira s pomočjo esteraz in alkalnega okolja v tankem črevesju, medtem ko preostanek vstopi v kri v portalni veni.
English: If you get severe or prolonged diarrhoea with Skilarence, other medicines may not work as well as they should.
Slovenian: Če se med jemanjem zdravila Skilarence pri vas pojavi huda ali dalj časa trajajoča driska, druga zdravila morda ne bodo delovala tako učinkovito, kot bi morala.
English: However, if you become flushed and get any of the following signs: - wheezing, difficulty breathing or shortness of breath, - swelling of the face, lips, mouth or tongue stop taking Skilarence and call a doctor straight away.
Slovenian: Če zardevate ali opazite katerega od naslednjih znakov: - sopenje, težave z dihanjem ali zasoplost, - otekanje obraza, ustnic, ust ali jezika prenehajte jemati zdravilo Skilarence in takoj pokličite zdravnika.
English: Animal studies have shown reproductive toxicity (see section 5.3).
Slovenian: Študije na živalih so pokazale toksičen vpliv na sposobnost razmnoževanja (glejte poglavje 5.3).
English: The most common adverse reactions observed with Skilarence in the Phase III clinical study (1102) in psoriasis patients were gastrointestinal events (62.7%), flushing (20.8%) and lymphopenia (10.0%).
Slovenian: Najpogostejši neželeni učinki, ki so jih opazili pri zdravilu Skilarence v III. fazi klinične študije (1102) s psoriatičnimi bolniki, so bili neželeni učinki na prebavila (62,7 %), vročinsko oblivanje (20,8 %) in limfopenija (10,0 %).
English: 40 gastro-resistant tablets 70 gastro-resistant tablets 90 gastro-resistant tablets 100 gastro-resistant tablets 120 gastro-resistant tablets 180 gastro-resistant tablets 200 gastro-resistant tablets 240 gastro-resistant tablets 300 gastro-resistant tablets 360 gastro-resistant tablets 400 gastro-resistant tablets
Slovenian: 40 gastrorezistentnih tablet 70 gastrorezistentnih tablet 90 gastrorezistentnih tablet 100 gastrorezistentnih tablet 120 gastrorezistentnih tablet 180 gastrorezistentnih tablet 200 gastrorezistentnih tablet 240 gastrorezistentnih tablet 300 gastrorezistentnih tablet 360 gastrorezistentnih tablet 400 gastrorezistentnih tablet
English: There is no evidence for Skilarence interaction with cytochrome P450 and the most common efflux and uptake transporters, thus no interactions are expected with medicinal products metabolised or transported by these systems (see section 5.2).
Slovenian: Ni dokazov o medsebojnem delovanju zdravila Skilarence s citokromom P450 in z najpogostejšimi efluksnimi transporterji in transporterji privzema, zato ne pričakujemo medsebojnega delovanja z zdravili, ki se presnavljajo ali prenašajo prek teh sistemov (glejte poglavje 5.2).
English: The plasma protein binding of monomethyl fumarate is around 50%.
Slovenian: Vezava monometilfumarata na človeške plazemske beljakovine je približno 50 %.
English: The biotransformation of dimethyl fumarate does not involve cytochrome P450 isoenzymes.
Slovenian: Biotransformacija dimetilfumarata ne vključuje izoencimov citokroma P450.
English: Other haematological disorders
Slovenian: Druge hematološke motnje
English: Prior and concomitant treatment with immunosuppressive or immunomodulating therapies Limited data are available on the efficacy and safety of Skilarence in patients who have been previously treated with other immunosuppressive or immunomodulating therapies.
Slovenian: Predhodno in sočasno zdravljenje z imunosupresivnimi ali imunomodulirajočimi zdravili O učinkovitosti in varnosti zdravila Skilarence pri bolnikih, ki so bili predhodno zdravljeni z imunosupresivnimi ali imunomodulirajočimi zdravili, je na voljo malo podatkov.
English: In vitro studies have shown that dimethyl fumarate at a therapeutic dose does not inhibit CYP3A4/5 and BCRP and is a weak P-glycoprotein inhibitor.
Slovenian: Študije in vitro so pokazale, da dimetilfumarat v terapevtskem odmerku ne zavira CYP3A4/5 in BCRP in je šibek zaviralec P-glikoproteina.
English: If you have severe side effects after an increase in dose, your doctor may recommend that you temporarily go back to the last dose.
Slovenian: Če se bodo po povečanju odmerka pri vas pojavili hudi neželeni učinki, vam bo zdravnik morda priporočil začasno vrnitev na zadnji odmerek.
English: In the event of a clinically relevant change in hepatic parameters, particularly in the absence of alternative explanations, consideration should be given to dose reduction or treatment discontinuation.
Slovenian: V primeru klinično pomembne spremembe jetrnih parametrov, zlasti, če ni alternativne razlage, je treba razmisliti o zmanjšanju odmerka ali prekinitvi zdravljenja.
English: 40, 70, 90, 100, 120, 180, 200, 240, 300, 360 and 400 gastro-resistant tablets in PVC/PVDC-aluminium blister packs.
Slovenian: 40, 70, 90, 100, 120, 180, 200, 240, 300, 360 in 400 gastrorezistentnih tablet v pretisnih omotih PVC/PVDC-aluminij.
English: Hepatic enzymes increased Serum creatinine increased*
Slovenian: Preiskave povišane vrednosti jetrnih encimov povišane vrednosti kreatinina v serumu*
English: Opportunistic infections/progressive multifocal leukoencephalopathy (PML) Cases of opportunistic infections, particularly of progressive multifocal leukoencephalopathy (PML) have been reported with other dimethyl fumarate-containing products (see section 4.8).
Slovenian: Oportunistične okužbe/progresivna multifokalna levkoencefalopatija (PML) Pri uporabi drugih zdravil, ki so vsebovala dimetilfumarat, so poročali o primerih oportunističnih okužb, še zlasti o progresivni multifokalni levkoencefalopatiji (PML) (glejte poglavje 4.8).
English: No data are available on the efficacy and safety of Skilarence when taken concomitantly with other immunosuppressive or immunomodulating therapies (see section 4.5).
Slovenian: Podatkov o učinkovitosti in varnosti zdravila Skilarence ob sočasnem jemanju drugih imunosupresivnih ali imunomodulirajočih zdravil ni na voljo (glejte poglavje 4.5).
English: Do not crush, break, dissolve or chew your tablets, as they have a special coating to help prevent irritation of your stomach.
Slovenian: Tablet ne drobite, ne razpolavljajte, ne raztapljajte in ne žvečite, saj imajo posebno oblogo, ki preprečuje draženje črevesja.
English: Skilarence with alcohol
Slovenian: Zdravilo Skilarence skupaj z alkoholom
English: However, Skilarence has not been studied in patients with severe renal impairment, and some cases of renal toxicity have been reported during post-marketing surveillance with fumaric acid esters.
Slovenian: Vendar pa zdravila Skilarence niso preučevali pri bolnikih s hudo okvaro delovanja ledvic, v obdobju trženja zdravila pa so poročali o nekaj primerih ledvične toksičnosti z estri fumarne kisline.
English: Fanconi syndrome is a rare but serious kidney disorder which may occur with Skilarence.
Slovenian: Fanconijev sindrom je redka, a resna bolezen ledvic, ki se lahko pojavi ob zdravljenju z zdravilom Skilarence.
English: In rare cases hypophosphataemic osteomalacia with non-localised bone pain, elevated alkaline phosphatase in serum and stress fractures may occur.
Slovenian: V redkih primerih lahko pride do hipofosfatemične osteomalacije z nelokalizirano bolečino v kosteh, zvišanjem alkalne fosfataze v serumu in stresnimi zlomi.
English: During treatment
Slovenian: Med zdravljenjem
English: In the event of a clinically relevant change in renal function, particularly in the absence of alternative explanations, consideration should be given to dosage reduction or treatment discontinuation.
Slovenian: V primeru klinično pomembne spremembe v delovanju ledvic, zlasti, če ni alternativne razlage, je treba razmisliti o zmanjšanju odmerka ali prekinitvi zdravljenja.
English: If a particular dose increase is not tolerated, it may be temporarily reduced to the last tolerated dose.
Slovenian: Če bolnik ne prenaša posameznega povečanja odmerka, je odmerek mogoče začasno znižati na zadnji odmerek, ki ga je bolnik še prenašal.
English: It has not been studied in patients with pre-existing low leukocyte or lymphocyte counts.
Slovenian: Zdravila Skilarence niso preučili pri bolniki z obstoječim nizkim številom levkocitov ali limfocitov.
English: In vitro studies have shown that monomethyl fumarate at the therapeutic dose does not inhibit or induce any of the cytochrome P450 enzymes, it is not a substrate or inhibitor of P-glycoprotein and is not an inhibitor of the most common efflux and uptake transporters.
Slovenian: Študije in vitro so pokazale, da monometilfumarat v terapevtskem odmerku ne zavira ali inducira nobenega encima citokroma P450, da ni substrat ali zaviralec P-glikoproteina in da ni zaviralec najpogostejših efluksnih transporterjev in transporterjev privzema.
English: Skilarence 30 mg 42, 70 and 210 gastro-resistant tablets in PVC/PVDC-aluminium blister packs.
Slovenian: Skilarence 30 mg 42, 70 in 210 gastrorezistentnih tablet v pretisnih omotih PVC/PVDC-aluminij.
English: Skilarence is not recommended in women of child-bearing potential not using appropriate contraception.
Slovenian: Zdravila Skilarence ne uporabljajte pri ženskah v rodni dobi, ki ne uporabljajo učinkovite kontracepcije.
English: Taking these medicines with Skilarence could increase the risk of side effects on your immune system.
Slovenian: Jemanje teh zdravil skupaj z zdravilom Skilarence bi lahko povečalo tveganje za pojav stranskih učinkov na vaš imunski sistem.
English: Carcinogenicity
Slovenian: Karcinogeneza
English: Caution should be exercised when prescribing medicinal products with a narrow therapeutic index that require absorption in the intestinal tract.
Slovenian: Previdnost je potrebna pri predpisovanju zdravil z ozkim terapevtskim indeksom, ki se presnavljajo v prebavilih.
English: Skilarence tablets are used to treat moderate to severe plaque psoriasis in adults.
Slovenian: Tablete zdravila Skilarence se uporabljajo za zdravljenje zmerne do hude psoriaze v plakih pri odraslih.
English: Superiority testing vs placebo PASI 75, n (%) p-value a a
Slovenian: Testiranje superiornosti v primerjavi s placebom PASI 75, n (%) p-vrednost
English: What Skilarence is and what it is used for
Slovenian: Kaj je zdravilo Skilarence in za kaj ga uporabljamo
English: Skilarence is indicated for the treatment of moderate to severe plaque psoriasis in adults in need of systemic medicinal therapy.
Slovenian: Zdravilo Skilarence je indicirano za zdravljenje zmerne do hude psoriaze v plakih pri odraslih, ki potrebujejo zdravljenje s sistemskim zdravilom.
English: - Severe hepatic or renal impairment.
Slovenian: − Huda okvara jeter ali ledvic.
English: 42 gastro-resistant tablets 70 gastro-resistant tablets 210 gastro-resistant tablets
Slovenian: 42 gastrorezistentnih tablet 70 gastrorezistentnih tablet 210 gastrorezistentnih tablet
English: *Additional adverse reactions reported with Fumaderm, a related medicinal product containing dimethyl fumarate along with other fumaric acid esters.
Slovenian: *Dodatni neželeni učinki, o katerih so poročali pri zdravljenju z zdravilom Fumaderm, ki je podobno zdravilo, ki vsebuje dimetilfumarat, skupaj z drugimi estri fumarne kisline.
English: Data from the Phase III clinical study as well as from the literature show that changes in haematological parameters are most likely to occur during the first 3 months after starting treatment with dimethyl fumarate.
Slovenian: Podatki iz klinične študije III. faze in podatki iz literature kažejo, da se spremembe hematoloških parametrov najverjetneje pojavijo v prvih 3 mesecih po začetku zdravljenja z dimetilfumaratom.
English: Each gastro-resistant tablet contains 136.8 mg lactose (as monohydrate).
Slovenian: Ena gastrorezistentna tableta vsebuje 136,8 mg laktoze (v obliki monohidrata).
English: The portion of dimethyl fumarate that reacts with glutathione, forming a glutathione-adduct, is metabolised further to its mercapturic acid, which is excreted in the urine.
Slovenian: Del dimetilfumarata, ki reagira z glutationom in tvori adukt glutationa, se nadalje presnavlja v njegovo merkapturno kislino, ki se izloča z urinom.
English: A transient increase in mean values of eosinophils was noted as early as week 3, reached a maximum at week 5 and 8, and had returned to baseline values at week 16.
Slovenian: Že v tretjem tednu so opazili prehodno povečanje povprečnih vrednosti eozinofilcev, ki je doseglo največjo vrednost v 5. in 8. tednu, vrednosti pa so se vrnile na izhodiščne v 16. tednu.
English: Blue, film-coated, round, biconvex tablet with a diameter of approximately 11.6 mm.
Slovenian: Modra, filmsko obložena, okrogla, bikonveksna tableta s premerom približno 11,6 mm.
English: The NOAEL for maternal and embryo-foetal toxicity was 40 mg/kg/day, corresponding to 0.2-fold and 2.0-fold the human systemic exposure at the highest recommended dose (720 mg/day), as AUC and Cmax values, respectively.
Slovenian: NOAEL za maternalno in embriofetalno toksičnost je bil 40 mg/kg/dan, kar ustreza 0,2-kratni in 2,0- kratni sistemski izpostavljenosti pri človeku pri najvišjem priporočenem odmerku (720 mg/dan), kot vrednosti AUC in Cmax.
English: White, film-coated, round, biconvex tablet with a diameter of approximately 6.8 mm. Skilarence 120 mg
Slovenian: Bela, filmsko obložena, okrogla, bikonveksna tableta s premerom približno 6,8 mm. Skilarence 120 mg
English: In patients experiencing diarrhoea during Skilarence treatment, the effect of oral contraceptives may be reduced and additional barrier methods of contraception may be necessary (see section 4.5).
Slovenian: Pri bolnicah, pri katerih se med zdravljenjem z zdravilom Skilarence pojavi diareja, se lahko učinek peroralnih kontracepcijskih sredstev zmanjša, zato bo morda treba uporabiti alternativne pregradne kontracepcijske metode (glejte poglavje 4.5).
English: Skilarence contains lactose.
Slovenian: Zdravilo Skilarence vsebuje laktozo.
English: Skilarence may decrease leukocyte and lymphocyte counts (see section 4.8).
Slovenian: Zdravilo Skilarence lahko zmanjša število levkocitov in limfocitov (glejte poglavje 4.8).
English: Most patients had moderate psoriasis based on Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores at baseline: the mean PASI score at baseline was 16.35 and 60% of patients scored as moderate on the PGA.
Slovenian: Večina bolnikov je imela ob izhodišču zmerno psoriazo na podlagi ocene indeksa PASI [indeks jakosti psoriaze in telesne površine, prizadete s psoriazo] in ocene PGA [celostna ocena, ki jo poda zdravnik]: povprečna ocena PASI je v izhodišču znašala 16,35 in 60 % bolnikov je dobilo oceno PGA »zmerno«.
English: It is not known how commonly they occur.
Slovenian: Njuna pogostnost ni znana.
English: However, because renal elimination plays a minor role in the total clearance from plasma, it is unlikely that renal impairment may affect the pharmacokinetic characteristics of Skilarence (see section 4.2).
Slovenian: Ker pa izločanje skozi ledvice igra manjšo vlogo pri celokupnem očistku iz plazme, ni preveč verjetno, da bi okvara ledvic lahko vplivala na farmakokinetične lastnosti zdravila Skilarence (glejte poglavje 4.2).