natgillin/translations-raw huggingface dataset:
Available toxicology data in lactating cynomolgus monkeys have shown excretion of daclizumab in milk (for details see section 5.3).
Razpoložljivi toksikološki podatki pri doječih opicah cynomolgus kažejo na izločanje daklizumaba v mleko (za podrobnosti glejte poglavje 5.3).
There was limited exposure in patients over 55 years of age in clinical studies with daclizumab.
Izpostavljenost bolnikov, starih več kot 55 let, v kliničnih študijah z daklizumabom je bila omejena.
In a clinical study, patients (n=90) on long-term treatment with Zinbryta mounted appropriate immune responses to an inactivated trivalent seasonal influenza vaccine.
V klinični študiji so bolniki (n = 90), ki so se dolgotrajno zdravili z zdravilom Zinbryta, razvili ustrezne imunske odzive na inaktivirano trivalentno sezonsko cepivo proti gripi.
• The liquid is cloudy or contains floating particles.
• je tekočina motna ali vsebuje plavajoče delce.
Daclizumab was detected in the milk of 11/14 lactating monkeys at levels that were <0.122% of the maternal serum levels, with no adverse reactions observed in the off-spring.
Daklizumab so odkrili v mleku 11/14 opic v laktaciji v ravneh, ki so bile < 0,122 % ravni v serumu matere, brez neželenih učinkov pri potomcih.
Total lymphocyte counts returned to baseline levels approximately 8-12 weeks after the last dose of Zinbryta (150mg).
Skupno število limfocitov se je vrnilo na izhodiščne ravni približno 8 do 12 tednov po zadnjem odmerku zdravila Zinbryta (150 mg).
• your skin or the whites of the eyes turn yellow Increased tiredness, dark urine and skin or whites of the eyes turning yellow also may be symptoms of liver problems, see section above on liver problems.
• vaša koža ali očesne beločnice porumenijo Povečana utrujenost, temen urin in porumenitev kože ali očesnih beločnic so lahko tudi simptomi težav z jetri, glejte zgornje poglavje o težavah z jetri.
This is normal and the bubbles do not need to be expelled before your injection.
To je normalno; pred injiciranjem mehurčkov ni treba iztisniti.
In addition, the Card explains the need for monitoring of liver function and educates the patient on the importance of adherence to their monthly blood tests.
Na opozorilni kartici je poleg tega pojasnjena potreba po spremljanju delovanja jeter, bolnike pa izobražuje tudi o pomembnosti udeleževanja mesečnih krvnih preiskav.
Treatment should be initiated by a physician experienced in the management of multiple sclerosis.
Zdravljenje naj se začne pod nadzorom zdravnika, ki ima izkušnje z zdravljenjem multiple skleroze.
# Hazard ratio for the risk of relapse.
# Razmerje ogroženosti za tveganje za recidiv.
Zinbryta may cause serious liver problems that may be life-threatening or result in death.
Zdravilo Zinbryta lahko povzroči resne težave z jetri, ki so lahko življenjsko nevarne ali celo povzročijo smrt.
• Patient Card;
• opozorilno kartico za bolnika;
p<0.0001 * Rates and risk reductions/endpoints are calculated over the treatment period up to 144 weeks.
* Pogostnost in zmanjšanje tveganja/opazovani dogodki se izračunajo na obdobje do 144 tednov.
Stomach pain may also be a symptom of liver problems, see section above on liver problems.
Bolečina v trebuhu je lahko tudi simptom težav z jetri, glejte poglavje o težavah z jetri.
Patients treated with Zinbryta should be advised to report any symptoms of new or worsening depression, and/or suicidal ideation immediately to the prescribing physician.
Bolnike, ki se zdravijo z zdravilom Zinbryta, je treba opozoriti, da morajo takoj poročati o vseh novih ali poslabšanih simptomih depresije in/ali samomorilnih mislih zdravniku, ki je zdravilo predpisal.
If you are over 55 your doctor may still prescribe Zinbryta.
Če ste starejši od 55 let, vam lahko zdravnik kljub temu predpiše zdravilo Zinbryta.
As data on use of Zinbryta during pregnancy are limited, the risk to the baby and benefit to the mother should be taken into consideration.
Ker so podatki o uporabi zdravila Zinbryta med nosečnostjo omejeni, je treba upoštevati tveganje za dojenčka in koristi za mater.
The safety of doses above 300 mg administered subcutaneously and 400 mg intravenously have not been evaluated.
Varnosti odmerkov, večjih od 300 mg, apliciranih subkutano, in 400 mg, apliciranih intravensko, niso ovrednotili.
Keep the pack closed until you need to use a new syringe/pen.
Pakiranje naj bo zaprto, dokler ne potrebujete nove injekcijske brizge/novega injekcijskega peresnika.
In the DECIDE study (see section 5.1), patients were tested for anti-drug (daclizumab) antibodies at week 4 and approximately every 3 months thereafter.
V študiji DECIDE (glejte poglavje 5.1) so pri bolnikih testirali prisotnost protiteles proti zdravilu (daklizumab) v 4. tednu, nato pa približno vsake 3 mesece.
Treatment discontinuation is recommended in patients who reach ALT or AST >3 times the ULN regardless of bilirubin levels.
Prekinitev zdravljenja je priporočljiva pri bolnikih, ki dosežejo ALT ali AST, ki je >3-krat višja od ULN, ne glede na ravni bilirubina.
The European Medicines Agency has deferred the obligation to submit the results of studies with Zinbryta in one or more subsets of the paediatric population in treatment of multiple sclerosis (see section 4.2 for information on paediatric use).
Evropska agencija za zdravila je začasno odložila zahtevo za predložitev rezultatov študij z zdravilom Zinbryta za eno ali več podskupin pediatrične populacije z multiplo sklerozo (za podatke o uporabi pri pediatrični populaciji glejte poglavje 4.2).
Prior to launch of Zinbryta in each Member State the Marketing Authorisation Holder (MAH) must agree about the content and format of the educational programme, including communication media, distribution modalities, and any other aspects of the programme, with the National Competent Authority.
Pred prihodom zdravila Zinbryta na trg v vsaki državi članici mora imetnik dovoljenja za promet z zdravilom z nacionalnim pristojnim organom uskladiti vsebino in obliko izobraževalnega programa, vključno s sredstvi obveščanja, načini razdeljevanja in drugimi vidiki programa.
Table 4: SELECT study clinical and MRI results (at 52 weeks) Placebo
Preglednica 4: Klinični rezultati in rezultati MR slikanja v študiji SELECT (pri 52 tednih) Placebo
For patients who test positive for HBV or HCV infection, consultation with a physician with expertise in the treatment of HBV or HCV is recommended.
Pri bolnikih, ki imajo pozitiven test na okužbo s HBV ali HCV, je priporočljiv posvet z zdravnikom, izkušenim v zdravljenju HBV ali HBC.
Based on the cross-study population pharmacokinetic analysis, daclizumab pharmacokinetics were not influenced by age (range: 18 to 66 years; n=1670) or gender (n = 567 males and 1103 females).
Na podlagi medštudijske analize populacijske farmakokinetike na farmakokinetiko daklizumaba nista vplivala starost (razpon: 18 do 66 let; n = 1670) ali spol (n = 567 moških in 1103 žensk).
• Inform patients about the need for monitoring of liver function during treatment and for up to 6 months after the last dose of Zinbryta;
• obvestiti bolnike, da je treba spremljati delovanje jeter med zdravljenjem in še do 6 mesecev po zadnjem odmerku zdravila Zinbryta;
• decreases in the amount of white blood cells (these will show up in blood tests)
• zmanjšano število belih krvnih celic (to pokažejo krvne preiskave)
• The contraindication in all patients with pre-existing hepatic disease or hepatic impairment;
• kontraindikaciji pri vseh bolnikih z obstoječo boleznijo jeter ali okvaro jeter;
• Patients who had failed to respond to a full and adequate course (at least 1 year) of prior DMT treatment, having had at least 1 relapse in the previous year while on therapy, and at least 9 T2 hyperintense lesions in cranial MRI or at least 1 Gd-enhancing lesion, or having an unchanged or increased relapse rate in the prior year as compared to the previous 2 years.
• bolniki, ki se niso odzvali na poln in ustrezen (vsaj enoletni) predhodni cikel zdravljenja z DMT, ki so imeli vsaj 1 recidiv v prejšnjem letu med zdravljenjem, in vsaj 9 hiperintenzivnih lezij T2 na MR slikanju glave ali vsaj 1 lezijo, vidno z gadolinijem, ali ki so imeli nespremenjeno ali povečano stopnjo recidivov v prejšnjem letu v primerjavi s prejšnjima 2 letoma.
• Summary of Product Characteristics (SmPC) and Package Leaflet (PL);
• povzetek glavnih značilnosti zdravila (SmPC) in navodilo za uporabo (PIL);
There are no data on the effects of Zinbryta on human fertility.
Ni podatkov o vplivu zdravila Zinbryta na plodnost pri ljudeh.
Do not try to treat any side effects yourself, but contact your doctor or nurse.
Neželenih učinkov si ne poskušajte zdraviti sami, temveč se obrnite na zdravnika ali medicinsko sestro.
Prior to treatment initiation with Zinbryta, serum transaminases (ALT and AST) and total bilirubin levels should be obtained, and patients should be screened for Hepatitis B (HBV) and C (HCV).
Pred uvedbo zdravljenja z zdravilom Zinbryta je treba preveriti ravni serumskih transaminaz (ALT in AST) ter celotnega bilirubina, bolnike pa je treba presejati glede hepatitisa B (HBV) in C (HCV).
No meaningful differences in clinical efficacy or safety were observed among the subgroups of MS patients by weight quartile in the DECIDE study.
Pomembnih razlik v klinični učinkovitosti ali varnosti med podskupinami bolnikov z multiplo sklerozo glede na kvartile telesne mase v študiji DECIDE niso opazili.
Zinbryta should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Zdravilo Zinbryta se lahko uporablja med nosečnostjo le, ko prednosti upravičijo možno tveganje za plod.
In addition to this leaflet you will be given a Patient Card by your doctor.
Poleg tega navodila vam bo zdravnik dal tudi Opozorilno kartico za bolnika.
In two 9 month studies in monkeys there were no pre-neoplastic or neoplastic tissue observed.
V dveh 9-mesečnih študijah pri opicah niso opazili preneoplastičnega ali neoplastičnega tkiva.
You will be given a Patient Card with further information about the things to watch out for while taking Zinbryta.
Prejeli boste Opozorilno kartico za bolnika z dodatnimi informacijami o stvareh, na katere morate biti med uporabo zdravila Zinbryta pozorni.
Wipe your skin with an alcohol wipe.
Obrišite si kožo z alkoholnim robčkom.
Animal studies do not indicate direct or indirect harmful effects with respect to reprotoxicity (see section 5.3).
Študije na živalih ne kažejo neposrednih ali posrednih škodljivih učinkov na sposobnost razmnoževanja (glejte poglavje 5.3).
Choose an injection site and wipe the skin with an alcohol wipe.
Izberite mesto injiciranja in kožo obrišite z alkoholnim robčkom.
The efficacy of Zinbryta was demonstrated in two studies (SELECT and DECIDE) in patients with RMS.
Učinkovitost zdravila Zinbryta je bila dokazana v dveh študijah (SELECT in DECIDE) pri bolnikih z recidivno multiplo sklerozo.
It is recommended that patients should be trained in the proper technique for self-administering subcutaneous injection using the pre-filled syringe/pre-filled pen.
Priporoča se, da se bolnika nauči pravilne tehnike za samoinjiciranje subkutane injekcije z uporabo napolnjene injekcijske brizge/napolnjenega injekcijskega peresnika.
Zinbryta is injected monthly.
Zdravilo Zinbryta se injicira mesečno.
Potential adverse reactions beyond this level are expected to be consistent with the safety profile for daclizumab in MS patients.
Pričakuje se, da bodo možni neželeni učinki nad to ravnijo v skladu z varnostnim profilom za daklizumab pri bolnikih z multiplo sklerozo.
Following subcutaneous administration of daclizumab, the median time to reach maximum serum concentrations (Tmax) ranged from 5 to 7 days.
Po subkutanem dajanju daklizumaba je bil razpon mediane časa za doseganje največje koncentracije v serumu (tmax) od 5 do 7 dni.
Clicking Clicking Stops
Klikanje preneha
• increased tiredness
• povečana utrujenost
Refer to section below, ‘Educational Guidance', for details of the Hepatic Risk Management Guide for Physicians and Patient Card that are recommended for use with this medicine.
Glejte spodnje poglavje "Vodnik za usposabljanje" za podrobnosti o Vodniku za zdravnike pri obvladovanju tveganj za jetra in Opozorilni kartici za bolnika, ki se pri uporabi tega zdravila priporočata.
Do not use more than one pre-filled syringe per month.
Ne uporabite več kot 1 napolnjene injekcijske brizge na mesec.
Consistent with results from individual studies, a cross-study population pharmacokinetic analysis indicated that daclizumab exposure is more than dose-proportional in the 50 mg to 100 mg subcutaneous dose range and is dose proportional in the 100 mg to 300 mg subcutaneous dose range.
V skladu z rezultati posamičnih študij je medštudijska analiza populacijske farmakokinetike pokazala, da je izpostavljenost daklizumabu več kot sorazmerna z odmerkom pri subkutanem odmerku 50 mg do 100 mg, in da je sorazmerna z odmerkom v razponu subkutanega odmerka 100 mg do 300 mg.
If you need a vaccination, ask your doctor first because Zinbryta may affect how well vaccines work.
Če se morate cepiti, najprej vprašajte zdravnika, saj lahko zdravilo Zinbryta vpliva na način delovanja cepiva.
The safety and effectiveness of Zinbryta in this age group are not known.
Varnost in učinkovitost zdravila Zinbryta v tej starostni skupini nista bili dokazani.
These symptoms may suggest problems with your liver.
Ti simptomi lahko kažejo na težave z jetri.
Based on the cross-study population pharmacokinetic analysis, the clearance of daclizumab is 0.212 L/day with a terminal half-life value of approximately 21 days.
Na podlagi medštudijske analize populacijske farmakokinetike je očistek daklizumaba 0,212 l/dan z vrednostjo končnega razpolovnega časa približno 21 dni.
Figure 2: Proportion of patients with 24 week confirmed disability (DECIDE study)
Slika 2: Delež bolnikov s 24-tedensko potrjeno boleznijo (študija DECIDE)
If you do develop liver problems your MS doctor may stop your treatment with Zinbryta and refer you to a liver specialist (see section 4, Possible side effects).
Če se pojavijo težave z jetri, vas lahko vaš zdravnik za zdravljenje MS preneha zdraviti z zdravilom Zinbryta in vas napoti k specialistu za jetra (glejte poglavje 4, Možni neželeni učinki).
Preclinical safety studies were conducted in cynomolgus monkeys due to species specificity of daclizumab binding only to human or primate CD25.
Predklinične študije so izvedli na opicah vrste cynomolgus zaradi specifičnosti vrste pri vezavi daklizumaba samo na CD25 pri ljudeh ali primatih.
• The need to screen for hepatitis B and C prior to treatment initiation and to recommend patients who test positive for HBV or HCV infection to consult with a physician with expertise in the treatment of those conditions.
• potrebi presejanja za hepatitis B in C pred začetkom zdravljenja in o potrebi, da se bolniki, ki imajo pozitiven test na okužbo s HBV ali HCV, posvetujejo z zdravnikom, izkušenim v zdravljenju teh bolezni;
All physicians who intend to prescribe Zinbryta must ensure they are familiar with the Hepatic Risk Management Guide for Physicians for this medicinal product.
Vsi zdravniki, ki nameravajo predpisovati zdravilo Zinbryta, se morajo seznaniti z Vodnikom za zdravnike pri obvladovanju tveganj za jetra za to zdravilo.
Your doctor or nurse should train you to give yourself the injections.
Vaš zdravnik ali medicinska sestra vas bosta naučila, kako si zdravilo injicirate sami.
• skin rashes, including inflamed, irritated, itchy, dry or peeling skin (dermatitis, eczema,
• kožni izpuščaji, vključno z vneto, razdraženo, srbečo, suho kožo ali luščenjem kože (dermatitis,
Note: After the pen has been removed from the injection site, the needle cover will lock to protect against needle injury.
Opomba: Potem ko napolnjeni injekcijski peresnik odstranite z mesta injiciranja, se bo varovalo igle zaklenilo, s čimer vas bo zaščitilo pred poškodbo z iglo.
These may be signs of a serious liver problem.
To so lahko znaki resnih težav z jetri.
Step 2: Collect your supplies and wash your hands a. Find a well-lit area and a clean, flat surface, like a table, and collect all the supplies you will need to give yourself, or to receive, an injection.
2. korak: Priskrbite si pripomočke in si umijte roke a. Poiščite dobro osvetljeno, čisto, ravno površino, na primer mizo, in nanjo položite vse pripomočke, ki jih potrebujete za samoinjiciranje ali za injiciranje.
A dose dependent increase in incidence of microglial aggregates above background was observed in the brain and spinal cord of monkeys treated with ≥35 mg/kg, (AUC 27 times higher than the clinical dose).
Od odmerka odvisno povečanje incidence agregatov celic mikroglije glede na ozadje so opazili v možganih in hrbtenjači opic, tretiranih z ≥ 35 mg/kg, (AUC 27-krat večji kot pri kliničnem odmerku).
The other ingredients are sodium succinate, succinic acid, sodium chloride, polysorbate 80, water for injections (see section 2 ‘Zinbryta contains a small amount of sodium').
Druge sestavine zdravila so natrijev sukcinat, sukcinska kislina, natrijev klorid, polisorbat 80, voda za injekcije (glejte poglavje 2 ‘Zdravilo Zinbryta vsebuje majhno količino natrija').
• Check that the Zinbryta medicine is colourless or slightly yellow (See Figure E).
• Preverite, da je zdravilo Zinbryta brezbarvno ali rumenkasto (glejte sliko E).
Colourless to slightly yellow, clear to slightly opalescent liquid with pH 6.
Brezbarvna do rumenkasta, bistra do nekoliko motna tekočina s pH 6.
Treatment with Zinbryta 150 mg every 4 weeks versus placebo significantly reduced the annualised relapse rate (ARR) and risk of relapse compared to placebo.
Zdravljenje z zdravilom Zinbryta 150 mg vsake 4 tedne v primerjavi s placebom je značilno zmanjšalo letno stopnjo recidivov (ARRannualised relapse rate) in tveganje za recidiv v primerjavi s placebom.
The absolute bioavailability of daclizumab 150 mg subcutaneously administered was approximately 90% based on a cross-study population pharmacokinetic analysis of subcutaneous and intravenous dosing.
Absolutna biološka uporabnost daklizumaba 150 mg, apliciranega subkutano, je bila približno 90 % na podlagi medštudijske analize populacijske farmakokinetike subkutanega in intravenskega odmerjanja.
Daclizumab is a humanised IgG1 monoclonal antibody that binds to CD25 (IL-2Rα), and prevents IL-2 binding to CD25.
Daklizumab je humanizirano monoklonsko protitelo IgG1, ki se veže na CD25 (IL-2Rα) in prepreči vezavo IL-2 na CD25.
Cases occurred early after treatment initiation, in patients having received repeated treatment courses and several months after discontinuation.
Primeri so se pojavili kmalu po uvedbi zdravljenja, pri bolnikih, ki so prejeli več ciklov zdravljenja, in več mesecev po ukinitvi zdravila.
The safety of immunisation with live viral vaccines during treatment with Zinbryta has not been studied.
Varnosti imunizacije z živimi virusnimi cepivi med zdravljenjem z zdravilom Zinbryta niso preučevali.
You should see a yellow plunger.
Videti morate rumen bat.
After the needle is in, let go of your skin
Ko je igla vbodena, spustite kožo.
If serious infection develops, it could be necessary to withhold treatment with Zinbryta until the infection resolves.
Če se razvije resna okužba, je morda treba z zdravljenjem z zdravilom Zinbryta počakati, da okužba izzveni.
Tell your doctor if you are taking, have recently taken or might take any other medicines and herbal supplements.
Obvestite zdravnika, če jemljete, ste pred kratkim jemali ali pa boste morda začeli jemati katero koli drugo zdravilo ali pripravke rastlinskega izvora.
Slowly push the plunger all the way down until the syringe is empty.
Počasi potiskajte bat do konca navzdol, dokler ni injekcijska brizga prazna.
With your other hand, firmly grasp the needle cover and pull it straight off the needle (See Figure G).
Z drugo roko čvrsto primite pokrovček igle in ga povlecite naravnost z igle (glejte sliko G).
The study designs and baseline characteristics are presented in Table 3.
Zasnova študije in izhodiščne značilnosti so predstavljeni v preglednici 3.
If you have trouble handling the syringe/pen, tell your doctor or nurse who may be able to help.
Če imate težave z uporabo injekcijske brizge/injekcijskega peresnika, prosite za pomoč zdravnika ali medicinsko sestro, ki vam bosta morda lahko pomagala.
The needle cover will extend to cover the needle and will lock (See Figure I).
Varovalo igle bo pokrilo iglo in se zaklenilo (glejte sliko I).
Do not inject directly into your belly button.
Ne injicirajte neposredno v popek.
Keep the leaflet and Card with you during treatment and for 6 months after the last dose of Zinbryta, since side effects may occur even after you have stopped treatment.
Navodilo in kartico shranite med zdravljenjem in še 6 mesecev po zadnjem odmerku zdravila Zinbryta, saj se lahko neželeni učinki pojavijo tudi po tem, ko prenehate z zdravljenjem.
The MAH shall ensure that in each EU MS where Zinbryta is marketed, all prescribers are provided with an educational package, aiming at preventing and/or minimising the risk of serious hepatic injury (potentially life threatening or fatal) and informing the patients about the unpredictability of these events and containing the following elements:
Imetnik dovoljenja za promet z zdravilom mora zagotoviti, da bodo v vsaki državi članici EU, v kateri se trži zdravilo Zinbryta, vsi zdravniki, ki predpisujejo zdravilo, prejeli izobraževalno gradivo, ki je namenjeno preprečevanju oziroma zmanjševanju tveganja resnih poškodb jeter (ki so lahko življenjsko nevarne ali smrtne), in obveščanju bolnikov o nepredvidljivosti teh dogodkov.
Due to the risk of hepatic injury, the use of Zinbryta is restricted (see section 4.1).
Zaradi tveganja poškodb jeter je uporaba zdravila Zinbryta omejena (glejte poglavje 4.1).
Pre-filled syringes/Pre-filled pens contain a single dose only and should be discarded after use.
Napolnjena injekcijska brizga/napolnjen injekcijski peresnik vsebuje le en odmerek in jo/ga je treba po uporabi zavreči.
There was no apparent correlation of anti-drug antibodies or neutralising antibodies development to clinical response, adverse reactions, or pharmacodynamic profile of daclizumab.
Med razvojem protiteles proti zdravilu ali nevtralizirajočih protiteles in kliničnim odzivom, neželenimi učinki ali farmakodinamičnim profilom daklizumaba ni bilo očitne korelacije.
Serious liver problems can occur both early after starting treatment with Zinbryta, any time during treatment and several months after discontinuing treatment.
Resne težave z jetri se lahko pojavijo kmalu po začetku jemanja zdravila Zinbryta, kadar koli med zdravljenjem in še več mesecev po prenehanju jemanja zdravila.
Zinbryta has no or negligible influence on the ability to drive and use machines.
Zdravilo Zinbryta nima vpliva ali ima zanemarljiv vpliv na sposobnost vožnje in upravljanja strojev.
As an IgG1 monoclonal antibody, daclizumab is expected to undergo catabolism to peptides and amino acids in the same manner as endogenous IgG.
Kot monoklonsko protitelo IgG1 se pričakuje, da se daklizumab katabolično presnovi na peptide in aminokisline na enak način kot endogeni IgG.
These symptoms vary from patient to patient but usually involve problems such as difficulty with walking, vision and balance.
Ti simptomi se med bolniki razlikujejo, vendar običajno vključujejo težave s hojo,
Hold the Zinbryta pre-filled syringe at a 45°-90° angle to the injection site (see Figure I).
Zdravilo Zinbryta napolnjena injekcijska brizga držite pod kotom 45° do 90° na mesto injiciranja (glejte sliko I).
Mean change in MSIS-29 physical score
Povprečno zmanjšanje fizičnega seštevka MSIS-29
• The recommendation not to initiate Zinbryta in patients with ALT or AST ≥ 2 times the ULN, and to discontinue treatment in patients with ALT or AST > 3 times the ULN;
• priporočilu, naj se zdravilo Zinbryta ne uvaja pri bolnikih, ki imajo ALT ali AST ≥ 2-krat višjo od ULN, in naj se zdravljenje prekine pri bolnikih z AST ali ALT, ki je > 3-krat višja od ULN;