Dolostop 1 G 10 Envelopes Oral Solution 10 Ml

Dolostop (1 G 10 Envelopes Oral Solution 10 Ml)

ACTION AND MECHANISM

- Paracetamol is a derivative of para-aminophenol, with analgesic and antipyretic activity.

* Analgesic effect. Its mechanism of action is not completely clear, but it seems to be fundamentally mediated by the inhibition of cyclooxygenase at the central level, especially COX-2, decreasing the synthesis of prostaglandins. It also has a certain peripheral effect by blocking the generation of the painful nerve impulse. There is also a possible peripheral effect due to inhibition of prostaglandin synthesis, activation of the CB1 cannabinoid receptor, modulation of serotonergic or opioid signaling pathways, inhibition of nitric oxide synthesis, or substance P-induced hyperalgesia.

* Antipyretic effect. It acts on the hypothalamic thermoregulatory center, inhibiting the synthesis of prostaglandins and the effects of endogenous pyrogen, giving rise to peripheral vasodilatation, increased blood flow to the skin and increased sweating, which contribute to heat loss.

At the same dose, it is considered to have an analgesic and antipyretic potency similar to acetylsalicylic acid (ASA). The effects are maximum at 1-3 h and last for 3-4 h.

Unlike ASA and other NSAIDs, it does not have an appreciable anti-inflammatory activity, except in some non-rheumatic pathologies, although it is not important. An advantage over NSAIDs is that not only does it not inhibit prostaglandin synthesis at the gastric level, but it seems to increase it, so it does not give rise to gastro-injurious effects. Similarly, it lacks antiplatelet effects.

PHARMACOKINETICS

* Oral route: rapid and complete absorption after oral administration, with a bioavailability of 75-85%. After a 1000 mg dose, a cmax of 7.7-17.6 mcg/ml is obtained after 0.5-2 h. It presents an important saturable first-pass effect from doses of 2 g.

Effect of food: Food can reduce the rate of absorption of paracetamol, although it does not substantially change the amount absorbed.

- Distribution: after its systemic absorption it is widely distributed in most tissues, reaching concentrations similar to those in plasma. Your Vd is approximately 1 l/kg. It tends to accumulate especially in the liver and renal medulla. Distribution is moderately rapid, with a plasma t1/2 of 1-3 h, and may be even faster in adolescents. It presents low binding to plasmatic proteins, around 10%, and may be 20-40% in patients with acute overdose. It is capable of crossing the placenta and the blood-brain barrier, detecting CSF concentrations of 1.5 mcg/ml after iv infusion.

- Metabolism: undergoes intense hepatic metabolism (90-95%) through conjugation reactions, mainly with glucuronic acid and sulfate.

The metabolization pathways are saturable at high doses, especially sulfation, which causes it to be metabolized by alternative pathways by cytochrome P450 (CYP2E1) that generate hepatotoxic metabolites such as N-acetyl-P-benzoquinone imine (NAPBI), which consumes glutathione. in its removal. NAPBI is subsequently metabolized to cysteine ​​and mercapturic acid.

Enzyme inducing/inhibiting capacity: it does not seem to present significant effects.

- Elimination: metabolism and subsequent elimination in urine, mainly in the form of glucuroconjugated metabolites (60-70%), and to a lesser extent conjugated with sulfate (20-30%) and cysteine ​​(3%). Small unchanged amounts are obtained in urine (<3%). Its elimination t1/2 is 1.5-3 h. It presents a small excretion in bile (2.6%).

Pharmacokinetics in special situations:

- Children: neonates may have a somewhat longer t1/2 (4-11 h), while in older children it is similar to that in adults (around 1.5-4.2 h).

- Elderly: they may have a somewhat longer t1/2.

- Renal insufficiency: elimination may be decreased in patients with end-stage renal insufficiency (CrCl < 10 ml/min).

It is partially removed by hemodialysis, hemoperfusion, and peritoneal dialysis.

- Hepatic insufficiency: they may present a somewhat longer t1/2, although the conjugation capacity is not modified.

INDICATIONS

- Symptomatic treatment of pain of mild to moderate intensity, such as [HEADACHE], [ODONTALGIA], [DYSMENORHEA], [OSTEOMUSCULAR PAIN] such as [MUSCLE CONTRACTURE], [TORTICOLLIS], [LUMBALGIA], [ARTHRITIS] or [RHEUMATOID ARTHRITIS ], [NEURALGIA] such as [CIATICA], sore throat, [POST-OPERATIVE PAIN] or postpartum.

- Symptomatic treatment of [FEVER].

Dolostop 1 g oral solution: is indicated in adults and adolescents over 15 years of age and weighing over 50 kg.

POSOLOGY

- Adults :

The recommended dose is 500 mg - 1 g of paracetamol (1 sachet) every 4-6 hours, as needed, according to the intensity of the symptoms. In no case will exceed 3 g of paracetamol in 24 hours. The shots should be spaced at least 4 hours. Administration of high doses of paracetamol for prolonged periods of time should be avoided as the risk of liver damage is increased.

If the pain persists for more than 5 days, the fever lasts for more than 3 days, or the pain or fever worsens or other symptoms appear, the clinical situation should be evaluated.

For sore throat, it should not be administered for more than 2 consecutive days, without evaluating the clinical situation.

- Pediatric population :

Due to the severity of liver toxicity and death in children who have received excessive doses of acetaminophen, dosing should be based on weight and use calibrated measuring devices. Parents should also be warned that the risk of overdose and serious liver damage is increased when more than one paracetamol-containing medicinal product is administered concomitantly.

The recommended daily dose of paracetamol is approximately 60 mg/kg/day, divided into 4 or 6 daily doses, that is, 15 mg/kg every 6 hours or 10 mg/kg every 4 hours.

- Children between 33 kg and 42 kg in weight (10 to 12 years old, approx.): 500 mg of paracetamol per dose, every 6 hours, up to a maximum of 4 sachets per day.

- Children between 43 kg and 50 kg in weight (12 to 15 years old, approx.): 500 mg of paracetamol per dose, every 4-6 hours as needed, up to a maximum of 5 sachets (2,500 mg) per day. Or 650 mg of paracetamol per dose, every 6 hours, up to a maximum of 4 sachets (2,600 mg) per day.

- Adolescents over 15 years of age and weighing over 50 kg can follow the adult dosage.

Do not use in children for more than 3 consecutive days without evaluating the clinical situation.

DOSAGE IN RENAL FAILURE

"ORAL ADMINISTRATION"

- CLcr 50-90 ml/min: does not require dose adjustment.

- CLcr 10-50 ml/min: 500 mg/6 h.

- CLcr < 10 ml/min: 500 mg/8 h.

It is considered that occasional use does not require special precautions. However, in patients receiving long-term treatment with high doses, renal adverse reactions may appear, so it is recommended to monitor renal functionality.

DOSAGE IN LIVER FAILURE

Use only under medical supervision, evaluating liver function at the beginning of treatment and periodically throughout it.

It is recommended to avoid doses greater than 2 g/24 h (orally) or 3 g (iv), with a minimum interval of at least 8 h.

RULES FOR CORRECT ADMINISTRATION

Paracetamol can be taken with or without food. However, fasting oral administration accelerates the effects of paracetamol, although not its intensity.

If a faster effect is required, it is recommended to take it without food.

- Oral solution: the oral solution can be administered directly or diluted in water (preferably), milk or fruit juices.

CONTRAINDICATIONS

- [ALLERGY TO PARACETAMOL] or to any other component of the medication.

- Severe and active liver disease.

PRECAUTIONS

- [RENAL INSUFFICIENCY]. Patients treated with high doses for long periods of time could experience renal adverse reactions, so it is recommended to monitor renal functionality. Patients with end-stage renal failure (CLcr < 10 ml/min) should be separated by at least 8 h. No special problems are expected in case of occasional use.

- [HEPATOTOXICITY]. During the hepatic metabolism of paracetamol, hepatotoxic compounds such as N-acetyl-benzoquinone imine are generated. This compound is produced in small amounts through metabolism by cytochrome P450, a minor pathway for paracetamol. However, at high doses of paracetamol, saturation of the fundamental pathways (glucuronide and sulfate conjugation) can occur, increasing the role of this cytochrome, and the consequent production of benzoquinone. This substance is rapidly detoxified with reduced glutathione expenditure, transforming into cysteine ​​and mercapturic acid, which is eliminated in the urine. If benzoquinone production is excessive, glutathione depletion occurs in the hepatocyte, and consequent cell damage, which could lead to life-threatening toxicity.

In general, self-medication should be limited, and paracetamol should not be used for more than 10 days without medical advice, and as long as the symptoms that motivated its use persist. Likewise, it is not advisable to exceed the recommended daily doses of 4 g in adults or 60 mg/kg in children.

Due to its hepatotoxic effects, and taking into account its indications and the alternative of other analgesics and antipyretics, as a general rule it is recommended to avoid its use in patients with liver disease, including [LIVER FAILURE], [HEPATITIS] or [HEPATIC CIRRHOSIS], as well as in patients with other risks of liver damage, such as [CHRONIC ALCOHOLISM], [HYPOVOLEMIA], [DEHYDRATION] or [MALNUTRITION] with low glutathione levels, or treated with other hepatotoxic drugs.

In those patients in whom this is not possible, it is suggested to use it under medical criteria, after a careful evaluation of the benefit/risk ratio. It is recommended to evaluate liver function in these patients at the beginning of treatment and periodically throughout it. Likewise, the maximum doses to be used should not exceed 2 g/24 h (po) or 3 g/24 h (iv).

- Allergy to salicylates: Patients allergic to acetylsalicylic acid do not usually present cross hypersensitivity reactions with paracetamol. However, cases of mild bronchospasm have been reported in patients allergic to acetylsalicylic acid treated with paracetamol.

- [BLOOD DISCRASIAS]. Paracetamol has been related to hematological alterations such as [LEUCOPENIA], agranulocytosis or [NEUTROPENIA]. In the case of prolonged treatments, it may be necessary to perform periodic blood counts.

- Determination of pancreatic functionality. Paracetamol may interfere with the bentiromide test, since it is metabolized to arylamine, giving rise to a false increase in para-aminobenzoic acid. It is recommended to stop treatment with paracetamol at least three days before the test.

PRECAUTIONS RELATED TO EXCIPIENTS

- This medicine contains ethanol. It is recommended to review the composition to know the exact amount of ethanol per dose.

* Amounts less than 100 mg/dose are considered small and are not usually harmful, especially in children.

* Amounts greater than 100 mg/dose may be harmful for people with [CHRONIC ALCOHOLISM], and should also be taken into account in pregnant and lactating women, children, and in high-risk groups, such as patients with liver disease ([HEPATIC FAILURE ], [LIVER CIRRHOSIS], [HEPATITIS]) or [EPILEPSY].

* The amount of alcohol in this medication (well below the 3 g/dose limit) is not expected to impair the ability to drive or operate machinery, or interfere with the effects of other medications.

This medicine contains sorbitol (E-420). Patients with hereditary fructose intolerance should not take this medicine.

This medicine contains glucose. Patients with glucose or galactose malabsorption should not take this medication.

This medication can cause severe allergic reactions and bronchospasm because it contains ammonium sulfite caramel.

- This medicine contains sulphites. It can rarely cause severe allergic reactions and bronchial spasm, so it should be used with caution in patients with [ASTHMA].

- This medicine contains sorbitol. Patients with hereditary [FRUCTOSE INTOLERANCE] should not take this medication.

- This medicine contains glucose. Patients with glucose or galactose malabsorption should not take this medicine.

- This medicine contains glucose. Its use in oral liquids and pharmaceutical forms that remain in contact with the mouth for some time can harm the teeth.

ADVICE TO THE PATIENT

- It can be taken with or without food. Administration without food accelerates the analgesic effects, but not their intensity.

- Do not exceed the recommended doses, or use for more than 10 days without a doctor's recommendation. Discontinue treatment as soon as symptoms disappear.

- Consult your doctor and/or pharmacist if the pain continues after 5-10 days of treatment (3-5 days in children; 2 days in the case of pharyngeal pain), the fever lasts for more than 3 days, or symptoms worsen or new ones appear.

- Those patients who habitually consume alcohol in significant quantities (3 or more drinks daily) should limit the dose of paracetamol to avoid liver damage.

- In case of overdose, consult a doctor and/or pharmacist, even if no symptoms appear.

SPECIAL WARNINGS

- Although it does not considerably reduce inflammation, very positive effects have been obtained in arthritic processes of the knee, probably due to its analgesic effect.

- Monitoring:

* Renal function and blood count in patients treated for prolonged periods of time.

* Liver function at baseline and periodically in patients at high risk of hepatotoxicity.

INTERACTIONS

In general, interactions with acetaminophen are not expected to be serious, due to its occasional use. Only in those patients treated with high doses, especially if there are other risk factors for hepatotoxicity, or in long-term treatments, it is expected that interactions have clinical significance.

- NSAID. Paracetamol is usually used in combination with other analgesics, such as ibuprofen, for the treatment of febrile processes in children. However, it must be taken into account that its administration together with NSAIDs or salicylates at high doses and for prolonged periods of time could increase the risk of fever. risk of kidney damage. It is therefore recommended not to exceed the recommended doses and to limit joint treatment to the essential minimum.

- Oral anticoagulants. Contrary to what happens with NSAIDs and acetylsalicylic acid, paracetamol does not have antiplatelet activity nor does it affect blood coagulation per se, which is why it is used as the analgesic drug of choice in patients treated with oral anticoagulants.

However, in the case of prolonged treatments and high doses, but without entering into toxic doses, a slight hepatotoxic effect could be produced, characterized by the decrease in the production of hepatic coagulation factors, which is why the INR of these patients could be increased. with risk of hemorrhage.

Therefore, it is recommended to monitor this parameter in these patients treated with high doses. The risk seems insignificant in the case of punctual treatments or in prolonged treatments with doses < 2 g/24 h.

- Busulfan. Risk of toxicity from busulfan, as paracetamol reduces glutathione levels, a substance with which busulfan conjugates when it is eliminated. It is recommended to avoid the administration of paracetamol, or limit exposure if this is not possible, in the 72 hours before and during treatment with busulfan.

- Chloramphenicol. Paracetamol could favor the accumulation of chloramphenicol by decreasing its hepatic metabolism, with the risk of haematological toxicity. It is advisable to monitor the patient.

- Drugs that delay gastric emptying, such as anticholinergics or exenatide. This delay could slow down the absorption of paracetamol and the onset of the effect, rather than its intensity.

- Hepatotoxic drugs. Paracetamol at high doses exerts a hepatotoxic effect. It is recommended to avoid its joint administration with other hepatotoxic drugs, as well as with alcohol.

- Enzyme inducers (estrogenic oral contraceptives, barbiturates, carbamazepine, phenytoin, rifampicin). Paracetamol is partially metabolized by cytochrome P450, so its plasmatic levels and therapeutic effects could be reduced in case of administration together with a drug that potently induces the hepatic microsomal system. On the other hand, in case of paracetamol overdose, the inducer could increase liver toxicity as a consequence of a greater production of toxic metabolites generated by this enzymatic system.

- Enzyme inhibitors (imatinib, isoniazid, propranolol). Increases in paracetamol plasma levels have been reported by drugs with inhibitory activity on its metabolism.

- Reverse transcriptase inhibitors (didanosine, zidovudine). Paracetamol could potentiate the haematological toxicity of zidovudine. On the other hand, both didanosine and zidovudine could favor acetaminophen hepatotoxicity.

- Lamotrigine. Paracetamol could increase the metabolism of lamotrigine, reducing its therapeutic effects.

- Ion exchange resins (cholestyramine, colestipol). Possible decreased absorption of paracetamol. Distancing the administration one hour.

The studies carried out have verified the absence of significant pharmacokinetic interaction with adefovir, amantadine, H2 antihistamines or proton pump inhibitors, argatroban, chloroquine, erythromycin, lithium, methotrexate, oseltamivir, sucralfate, telmisartan or zolmitriptan. No interaction of any kind has been reported with alpha-1 adrenergic blockers (doxazosin, terazosin), furosemide, letrozole or zanamivir.

Paracetamol slightly reduces urinary excretion of diazepam, although plasma levels remain unchanged.

Paracetamol does not affect the immunogenicity of influenza vaccines, and could reduce the symptoms of their adverse reactions.

PREGNANCY

Animal Safety : Animal studies have not reported teratogenic effects.

Safety in Humans : A large body of data in pregnant women indicates the absence of fetal/neonatal toxicity or congenital malformations. Epidemiological studies on the neurodevelopment of children exposed to paracetamol in utero show inconclusive results.

Paracetamol crosses the placental barrier. Several cohort studies have been conducted on the safety of oral acetaminophen in pregnant women. These studies did not show an increased risk of birth defects, heart defects, or miscarriage. There are data that suggest that its use during the last two trimesters could be related to an increased risk of wheezing in the child's first year of life.

Some specific cases of serious adverse reactions have been reported in children of mothers who received paracetamol during pregnancy, including severe anemia, hepatotoxicity and nephrotoxicity (the latter two being fatal). However, these symptoms appeared to be due to an overdose on the mother's part.

Oral paracetamol, at the recommended doses and used occasionally, is considered a safe analgesic/antipyretic during pregnancy. It has been used just before delivery in women with fever secondary to chorioamnionitis, observing a significant improvement in the fetal and newborn status after normalization of maternal temperature. However, its use at high doses or for longer periods of time could be related to fetal hepatotoxicity phenomena.

On the contrary, due to the lack of safety and efficacy data in pregnant women, it is recommended to avoid its use by parenteral route, unless the expected benefits outweigh the possible risks.

Effects on Fertility : In animal studies, acetaminophen caused testicular atrophy and decreased spermatogenesis at high doses. Whether these data can be extrapolated to humans is unknown.

LACTATION

Paracetamol is excreted in small amounts in breast milk, reaching concentrations in milk of 10-15 mcg/ml (similar to plasma concentrations) within 1-2 h after a dose of 650 mg po Estimated exposure in the child 1-2% of the maternal dose. Paracetamol or its metabolites have not been found in infant urine, nor have adverse reactions been reported in children, except for one case of maculopapular rash, which resolved without sequelae when the mother discontinued paracetamol.

CHILDREN

Paracetamol is an analgesic-antipyretic drug commonly used in children, including young children. However, as a general precautionary measure, its use in children under 3 years of age should be carried out under medical supervision, and limit its use to the minimum possible.

Due to the risks of serious, potentially fatal poisoning, it is recommended to closely monitor the dosage in children, avoiding doses higher than those recommended. In this way, the appropriate presentation must be used that allows the child to be accurately dosed, based on its weight.

It is advisable to consult the dosage of the different presentations for more information on its use in children.

ELDERLY

Reduced clearance has been reported in elderly patients. Certain manufacturers recommend reducing the dose by 25% compared to young adults, but others do not consider this precaution necessary.

ADVERSE REACTIONS

Paracetamol is usually well tolerated, and its adverse reactions are rare.

Adverse reactions are described according to each frequency interval, being considered very common (>10%), common (1-10%), uncommon (0.1-1%), rare (0.01-0.1%). , very rare (<0.01%) or frequency unknown (cannot be estimated from the available data).

"ORAL RAM"

- Hepatic: rare [INCREASED TRANSAMINASES], [INCREASED ALKALINE PHOSPHATASE], [HIPERBILIRRUBINEMIA]; very rare [HEPATOTOXICITY], with [JAUNDICE].

- Cardiovascular: rare [HYPOTENSION].

- Neurological/psychological: [DIZZENESS], [DISORIENTATION], [EXCITABILITY].

- Genitourinary: very rare renal disorders such as cloudy urine and kidney disorders.

- Allergic: very rare [HYPERSENSITIVITY REACTIONS], with symptoms ranging from [SKIN ERUPTIONS] and [URTICARIA] to [ANAPHYLAXIS].

- Hematological: very rare [THROMBOCYTOPENIA], [AGRANULOCYTOSIS], [LEUKOPENIA], [NEUTROPENIA], [HEMOLYTIC ANEMIA], [METAHEMOGLOBINEMIA]. The prothrombin time could be increased, although it does not seem significant.

- Metabolic: very rare [HYPOGLYCEMIA].

- Analytical: analytical alterations have been described such as [INCREASE IN LACTATE DEHYDROGENASE], [INCREASE IN SERUM CREATININE], increase in ammonia levels, [INCREASE IN UREIC NITROGEN].

On the other hand, paracetamol could interfere with the analytical determination of uric acid and glucose, as well as with theophylline monitoring. It can also give false positives in the determination of 5-hydroxy-indoleacetic acid when nitrosonaphthol is used as a reagent.

- General: rare [GENERAL DISCOMFORT].

ADVERSE REACTIONS RELATING TO EXCIPIENTS

- This medicine contains sulphites. May rarely cause severe [HYPERSENSITIVITY REACTIONS] and [BRONCHIAL SPASM].

OVERDOSE

Symptoms: Paracetamol can lead to very serious and potentially fatal poisoning. Toxicity can begin to be experienced from single doses of 6 g in adults or 100 mg/kg in children. Doses greater than 20-25 g are potentially fatal. Chronic doses greater than 4 g/24 h may cause transient hepatotoxicity. However, patients treated with other hepatotoxic drugs, enzyme inducers, or with chronic alcoholism could be more susceptible to its toxic effects, requiring lower doses to produce toxicity.

Hepatotoxicity can appear at Cp of paracetamol greater than 120 mcg/ml at 4 h and 30 mcg/ml at 12 h. Levels of 300 mcg/ml 4 hours after overdose have been associated with hepatotoxicity phenomena in 90% of patients.

Acetaminophen overdose follows four characteristic clinical stages:

- Phase I: appears a few hours after the overdose, and up to the first 24 hours. It presents with general malaise, nausea and vomiting, abdominal pain, paleness, excessive sweating and anorexia. Liver functionality and liver parameters are normal.

- Phase II: occurs 24-36 hours after overdose. Symptoms of liver damage begin to appear, such as abdominal pain in the right upper quadrant and increased transaminase and bilirubin levels and prothrombin time.

- Phase III: occurs 72-96 h after overdose, and coincides with the peak of hepatotoxicity, with transaminase elevations of up to 10,000 U/l and even higher, increases in bilirubin, glucose, lactate and phosphate, as well as elevation of prothrombin time. The patient may present with encephalopathy and coma. Likewise, renal tubular necrosis and myocardial involvement have been reported on occasions. Death from fulminant hepatic failure with hepatic necrosis may occur.

- Phase IV: occurs 7-8 days after overdose. Recovery of those patients who have survived the previous stage.

The risk of severe poisoning by paracetamol depends on the route of administration as well as the conditions of use of the drug. In this way, it is not to be expected that serious poisoning occurs in the event of overdose with suppositories (yes by ingesting them, although this is not frequent), or in the case of injectables (due to their hospital use, with sanitary control , despite the fact that serious poisonings have occurred due to confusion of the dose in the amount of paracetamol or volume of the injectable solution). However, in no case can it be ruled out.

Treatment: in case of oral overdose, and preferably within 4 hours after ingestion, gastric aspiration and lavage will be carried out, together with administration of activated carbon, reducing the absorption of paracetamol.

N-acetylcysteine ​​is the specific antidote for paracetamol overdose. N-acetylcysteine ​​can be used orally in adults and parenterally in adults and children.

- IV route: the dose to be administered is 300 mg/kg, for a period of 20 hours and 15 minutes, according to the following schedule:

* Adults: initially 150 mg/kg (equivalent to 0.75 ml/kg of 20% aqueous solution, with pH 6.5) by slow IV route or diluted in 200 ml of 5% glucose serum, over 15 min.

Then 50 mg/kg (0.25 ml/kg of 20% aqueous solution, pH 6.5) diluted in 500 ml of 5% glucose serum as an IV infusion over 4 h.

Finally, 100 mg/kg (0.50 ml/kg of a 20% aqueous solution, with pH 6.5) diluted in 1000 ml of 5% glucose serum as an IV perfusion for 16 h.

* Children: the same regimen will be administered, although the volume of the infusion solutions will be adjusted to the age and weight of the child to avoid pulmonary vascular congestion.

The efficacy of parenteral treatment with N-acetylcysteine ​​is greatest when administered within 8 hours of overdose, gradually decreasing thereafter until it is ineffective by 15 hours.

The administration of N-acetylcysteine ​​may be suspended when paracetamol plasma levels are less than 200 mcg/ml.

- Oral route (only for adults): initially 140 mg/kg, followed by 17 doses of 70 mg/kg/4 h. The dose should be diluted in water, cola, or orange or grape juice to a final concentration of 5%, as it has an unpleasant taste and may cause irritation or sclerosing. If the dose is vomited within 1 h, its administration will be repeated.

If necessary, it will be administered diluted in water through a duodenal tube.

If the patient experiences symptoms of hepatotoxicity, liver function should be monitored every 24 hours.

Dolostop Leaflet  (1 G 10 Envelopes Oral Solution 10 Ml)