Desflurane

Pharmaceuticals -> Nervous system -> Anesthetics

Pharmaceuticals -> Anesthetics

Pharmaceuticals

1.44

Relative density (water = 1): 1.5

Negligible

3.54e+00 g/L

Solubility in water: poor

Breast Feeding; Lactation; Anesthetics, Inhalation

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

23.5 °C

23.5 °C

23.5 °C

74.3 °F

88.53 kPa at 20 °C; approximately 700 mm Hg at 22-23 °C

Vapor pressure, kPa at 20 °C: 89

700 [email protected] °F

Liquid

COLOURLESS LIQUID.

Colorless liquid.

Volatile

Partition coefficient at 37 °C: (blood/gas): 0.424; (saline/gas): 0.225; (oil/gas): 18.7

Hydroxyl radical reaction rate constant = 4.40X10-15 cu cm/molec-sec at 25 °C

This chemical does not meet GHS hazard criteria for 20% (1 of 5) of reports.

Danger

H315 (40%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P260, P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 5 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including desflurane, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

No discernible degradation occurs in the presence of strong acids. Desflurane does not corrode stainless steel, brass, aluminum, anodized aluminum, nickel plated brass, copper, or beryllium.

Desflurane is chemically stable. The only known degradation reaction is through prolonged direct contact with soda lime producing low levels of fluoroform (CHF3). The amount of CHF3 obtained is similar to that produced with MAC-equivalent doses of isoflurane.

Fresh air, rest. Artificial respiration may be needed. Refer for medical attention.

Remove contaminated clothes. Rinse and then wash skin with water and soap.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Rinse mouth. Refer for medical attention .

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing. Move containers from fire area if you can do so without risk.

Water fog, dry chemical, or carbon dioxide as appropriate for surrounding fire and materials. Do not use water jet as an extinguisher, as this will spread the fire.

Store at room temperature, 15 -30 °C (59-86 °F). SUPRANE (desflurane, USP) has been demonstrated to be stable for the period defined by the expiration dating on the label. The bottle cap should be replaced after each use of SUPRANE.

Store in tight container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.

Collect and reclaim or dispose in sealed containers at licensed waste disposal site. This product, in its present state, when discarded or disposed of, is not a hazardous waste according to Federal regulations (40 CFR 261.4 (b)(4)). Under RCRA, it is the responsibility of the user of the product to determine, at the time of disposal, whether the product meets RCRA criteria for hazardous waste. Dispose in accordance with all applicable regulations.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.

As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Clean equipment and work surfaces with suitable detergent or solvent after use. After removing gloves, wash hands and other exposed skin thoroughly.

In the event of overdosage, or suspected overdosage, take the following actions: discontinue administration of Desflurane, maintain a patent airway, initiate assisted or controlled ventilation with oxygen, and maintain adequate cardiovascular function. (L1712)

Anesthetic concentrations of desflurane at equilibrium (administered for 15 or more minutes before testing) reduced the ED95 of succinylcholine by approximately 30% and that of atracurium and pancuronium by approximately 50% compared to N2O/opioid anesthesia. The effect of desflurane on duration of nondepolarizing neuromuscular blockade has not been studied.

Benzodiazepines (midazolam 25-50 ug/kg) decrease the MAC of desflurane by 16% as do the opioids (fentanyl 3-6 ug/kg) by 50%.

We investigated effects of vitamin C and E (VCE) administration on desflurane-induced oxidative toxicity and element changes in the blood of operative patients under desflurane general anesthesia. Forty American Society of Anesthesiologists I or II Physical Status adult patients were scheduled for elective surgery. The patients were randomly divided into two groups. Control and VCE group was introduced to anesthesia with desflurane. VCE was administreted to patients in the control and VCE group before 1 hour of anesthesia with desflurane. Baseline (preoperative) and postoperative (at the 1(st), the 24(th), and 72(th) hr), blood samples were taken from the first and second groups. Erythrocyte and plasma lipid peroxidation levels at the 1(st), 24(th), and 72(th) hours were higher in the control than in baseline group, although their levels at the same periods were lower in the VCE group than in the control. Vitamin E levels at the postoperative 1(st) and 24(th) hours and erythrocyte glutathione peroxidase (GSH-Px) activity at the postoperative 1(st), 24(th), and 72(th) hours was lower than in baseline values. Erythrocyte GSH-Px activity and plasma vitamins A, C, and E levels at the postoperative 1(st), 24(th), and 72(th) hours were higher in the VCE group than in the control group. Erythrocyte and plasma reduced glutathione, plasma ?-carotene, and serum copper, while zinc, selenium, aluminum, iron, magnesium, and calcium levels did not differ between preoperative and postoperative periods in both groups. In conclusion, VCE combination prevented the desflurane-induced vitamin E and GSH-Px consumptions to strengthen the antioxidant levels in the blood of operative patients.

Prospective, serial blood testing often demonstrates minor transient elevations in serum aminotransferase levels in the 1 to 2 weeks after major surgery and use of halogenated anesthetics. Appearance of ALT levels above 10 times the upper limit of normal, however, is distinctly unusual and points to significant hepatotoxicity. Clinically apparent, severe hepatic injury from desflurane is very rare, with only isolated case reports having been published and not all of which were very convincing. The injury is marked by acute elevations in serum aminotransferase levels (5- to 50-fold) and appearance of jaundice within 2 to 21 days of surgery. There are usually minimal increases in alkaline phosphatase and gammaglutamyl transpeptidase levels. Jaundice is usually preceded by a day or two of fever and may be accompanied by rash and eosinophilia. The acute liver injury may be self-limited and resolve within 4 to 8 weeks, but can be severe and associated with acute liver failure. A strong risk factor is previous exposure to any of the halogenated anesthetics and particularly a history of halothane hepatitis or unexplained fever and rash after anesthesia with one of these agents. The differential diagnosis of acute liver injury after surgery and anesthesia is often challenging, and a clinical picture similar to desflurane induced hepatitis can be caused by shock or ischemia, sepsis, acetaminophen overdose, acute viral or herpes hepatitis, as well as other idiosyncratic forms of drug induced liver injury.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 98(SRC), determined from a structure estimation method(2), indicates that desflurane is expected to have very high mobility in soil(SRC). Volatilization of desflurane from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.1X10-2 atm-cu m/mole(SRC), derived using a fragment constant estimation method(3). Desflurane is expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 664 mm Hg at 20 °C(4). Biodegradation data in soil were not available(SRC, 2012).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 98(SRC), determined from a structure estimation method(2), indicates that desflurane is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 7.1X10-2 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.3 hours and 5 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 2.8(SRC), from an estimated log Kow of 2.8(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2012).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), desflurane, which has a vapor pressure of 664 mm Hg at 20 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase desflurane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 5 years(SRC), calculated from its rate constant of 4.40X10-15 cu cm/molecule-sec at 25 °C(3). Desflurane does not contain chromophores that absorb at wavelengths >290 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Desflurane, along with the other inhalational agents, sevoflurane and isoflurane, is a potent vasodilator and can cause a decrease in blood pressure by decreasing systemic vascular resistance. A concomitant increase in heart rate sometimes occurs. Cardiac output is typically preserved with the use of this agent. Desflurane dilates cerebral arteries and decreases the cerebral metabolic rate.

The substance can be absorbed into the body by inhalation of its vapour and by ingestion.

Rapidly absorbed into the circulation via the lungs following inhalation.

Desflurane is the most likely inhaled anesthetic to result in CO production, compared with isoflurane and sevoflurane. The production of CO is by the degradation of desflurane by desiccated CO2 absorbent, barium hydroxide lime. The drug can produce clinically significant levels of CO, stressing the importance of replacing dried CO2 absorbents.

Desflurane induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Desflurane also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane. It also appears to bind the D subunit of ATP synthase and NADH dehydogenase. Desflurane also binds to and agonizes the GABA receptor, the large conductance Ca²⁺ activated potassium channel, the glycine receptors, and antagonizes the glutamate receptors.

Cough. Sore throat. Dizziness. Drowsiness. Headache. Unconsciousness.

Dry skin. Redness.

Redness. Pain.

See Inhalation.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of desflurane can be estimated to be 98(SRC). According to a classification scheme(2), this estimated Koc value suggests that desflurane is expected to have high mobility in soil.

/HUMAN EXPOSURE STUDIES/ We examined the potential toxicity of desflurane in 13 young 25.0 +/- 2.3 (mean +/- SD) yr-old men, given 7.35 +/- 0.81 MAC-hours of desflurane anesthesia. Hepatic and renal function tests, serum electrolytes, and standard urine and hematologic tests were performed before, during, and after anesthesia. No toxicity was found. There were no changes in tests of hepatocellular integrity (plasma alanine transferase activity), synthetic function (serum albumin, prothrombin time, partial thromboplastin time), or renal function (serum creatinine concentration, blood urea nitrogen concentration). Decreases in red blood cell count, hematocrit, and blood hemoglobin concentration during and immediately after anesthesia were attributed to blood sampling and infusion of intravenous electrolyte solution. These values returned by 4 days after anesthesia to values not different from those before anesthesia. Increased white blood cell counts and blood glucose concentrations noted during anesthesia with other inhaled anesthetics were also seen in these volunteers. Desflurane appears to have no greater toxicity than currently used inhaled anesthetics and, because of its lesser metabolism, may have lesser or not toxicity.

/HUMAN EXPOSURE STUDIES/ Eight patients receiving SUPRANE (desflurane, USP) were compared to six patients receiving isoflurane, all with chronic hepatic disease (viral hepatitis, alcoholic hepatitis, or cirrhosis). No differences in hematological or biochemical tests, including hepatic enzymes and hepatic function evaluation, were seen.

/HUMAN EXPOSURE STUDIES/ Nine patients receiving SUPRANE (desflurane, USP) (N=9) were compared to 9 patients receiving isoflurane, all with chronic renal insufficiency (serum creatinine 1.5-6.9 mg/dL). No differences in hematological or biochemical tests, including renal function evaluation, were seen between the two groups. Similarly, no differences were found in a comparison of patients receiving either SUPRANE (desflurane, USP) (N=28) or isoflurane (N=30) undergoing renal transplant.

/HUMAN EXPOSURE STUDIES/In an open-labelled clinical trial, the effect of desflurane anesthesia on liver function markers in pediatric patients was monitored. Fifty infants and children, 37 male, scheduled for elective cleft plate surgery were included in the study. Median age was 0.57 (0.25-5.45) years (range), mean desflurane exposure was 2.29 +/- 0.75 MAC-hr. Function markers were determined within 24 hr prior to and within 24-48 hr after anaesthesia. Complete data sets were available for total bilirubin 29, aspartate aminotransferase (ASAT) 36, alanine aminotransferase (ALAT) 35, and for alkaline phosphatase (AP) 28. Pre- and postanesthetic function tests were compared by means of Wilcoxon's matched-pairs test. Only for AP could a statistically significant reduction of the postanesthetic values be observed, while the other parameters showed no significant changes. Postanesthetic ASAT and ALAT were clearly reduced in three children who had unspecific highly elevated preanesthetic values. After the study, this observation could be repeated in at least one child, who received a further anesthesia with desflurane within 3 months. The data suggest that desflurane does not affect excretory or structural liver integrity in infants and children.

For more Human Toxicity Excerpts (Complete) data for Desflurane (7 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including desflurane, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N01AB07

N - Nervous system

QN - Nervous system

Desflurane is a general inhalation anesthetic. It has a short duration of action as it is rapidly cleared. Patients should be counselled regarding the risks of malignant hyperthermia, perioperative hyperkalemia, respiratory adverse reactions in pediatric patients, QTc prolongation, hepatobiliary disorders, pediatric neurotoxicity, and postoperative agitation in children.

The mechanism of inhalational anesthetics is still not fully understood. They can block excitatory ion channels and increase the activity of inhibitory ion channels. The most notable agonism is at the GABA_A channel. Desflurane is also an agonist of glycine receptors, antagonist of glutamate receptors, inducer of potassium voltage gated channels, and inhibits both NADH-ubiquinone oxioreductase chain 1 and calcium transporting ATPases. An older school of thought is the unitary theory of general anesthetic action, suggesting that desflurane affects the lipid bilayer of cells. Studies of other halogenated inhalational anesthetics have shown that the lipid bilayer spreads out more thinly as the anesthetic incorporates into the bilayer. However, the anesthetic does not bind to lipid heads or acyl chains of hydrocarbons in the bilayer. The effect of incorporating into the lipid bilayer is not well described. By incorporating into the lipid bilayer, anesthetics may introduce disorder in the lipids, leading to some indirect effect on ion channels. However, this theory remains controversial.

Desflurane is minimally defluorinated by CYP2E1, to the extent that serum fluoride levels do not increase above baseline levels.

Renal and hepatic toxicity of the fluorinated ether volatile anesthetics is caused by biotransformation to toxic metabolites. Metabolism also contributes significantly to the elimination pharmacokinetics of some volatile agents. Although innumerable studies have explored anesthetic metabolism in animals, there is little information on human volatile anesthetic metabolism with respect to comparative rates or the identity of the enzymes responsible for defluorination. The first purpose of this investigation was to compare the metabolism of the fluorinated ether anesthetics by human liver microsomes. The second purpose was to test the hypothesis that cytochrome P450 2E1 is the specific P450 isoform responsible for volatile anesthetic defluorination in humans. Microsomes were prepared from human livers. Anesthetic metabolism in microsomal incubations was measured by fluoride production. The strategy for evaluating the role of P450 2E1 in anesthetic defluorination involved three approaches: for a series of 12 human livers, correlation of microsomal defluorination rate with microsomal P450 2E1 content (measured by Western blot analysis), correlation of defluorination rate with microsomal P450 2E1 catalytic activity using marker substrates (para-nitrophenol hydroxylation and chlorzoxazone 6-hydroxylation), and chemical inhibition by P450 isoform-selective inhibitors. The rank order of anesthetic metabolism, assessed by fluoride production at saturating substrate concentrations, was methoxyflurane > sevoflurane > enflurane > isoflurane > desflurane > 0. There was a significant linear correlation of sevoflurane and methoxyflurane defluorination with antigenic P450 2E1 content (r = 0.98 and r = 0.72, respectively), but not with either P450 1A2 or P450 3A3/4. Comparison of anesthetic defluorination with either para-nitrophenol or chlorzoxazone hydroxylation showed a significant correlation for sevoflurane (r = 0.93, r = 0.95) and methoxyflurane (r = 0.78, r = 0.66). Sevoflurane defluorination was also highly correlated with that of enflurane (r = 0.93), which is known to be metabolized by human P450 2E1. Diethyldithiocarbamate, a selective inhibitor of P450 2E1, produced a concentration-dependent inhibition of sevoflurane, methoxyflurane, and isoflurane defluorination. No other isoform-selective inhibitor diminished the defluorination of sevoflurane, whereas methoxyflurane defluorination was inhibited by the selective P450 inhibitors furafylline (P450 1A2), sulfaphenazole (P450 2C9/10), and quinidine (P450 2D6) but to a much lesser extent than by diethyldithiocarbamate. These results demonstrate that cytochrome P450 2E1 is the principal, if not sole human liver microsomal enzyme catalyzing the defluorination of sevoflurane. P450 2E1 is the principal, but not exclusive enzyme responsible for the metabolism of methoxyflurane, which also appears to be catalyzed by P450s 1A2, 2C9/10, and 2D6. The data also suggest that P450 2E1 is responsible for a significant fraction of isoflurane metabolism. Identification of P450 2E1 as the major anesthetic metabolizing enzyme in humans provides a mechanistic understanding of clinical fluorinated ether anesthetic metabolism and toxicity.

SUPRANE (desflurane, USP) is a volatile liquid inhalation anesthetic minimally biotransformed in the liver in humans.

Biotransformation and hepatotoxicity of desflurane were evaluated in the guinea pig liver slice culture system. Liver slices (250-300 microns) were prepared from 600-650-g male Hartley guinea pigs. The slices were incubated in sealed vials in a Krebs-Henseleit buffer at 37 degrees C under 95% O2. Desflurane was vaporized to produce media concentrations of 0.7-2.3 mM. After incubation (3-24 hr) viability of the slices was determined (K+ content; protein synthesis secretion) along with the biotransformation of desflurane (F-). Isoflurane (2.3 mM) was included in the studies for comparative purposes. Although desflurane caused a mild concentration-related reduction in slice K+ content (1.1-2.2 mM; 20%-40% of control), the effects were less than those produced by 2.3 mM isoflurane (50% of control). High concentrations of desflurane decreased protein synthesis at the first 9 hr of incubation, and isoflurane decreased protein synthesis throughout the incubation period. Neither anesthetic affected protein secretion. The biotransformation of desflurane was minimal with threefold less F- produced from desflurane than isoflurane.

The metabolism of desflurane has been assessed both in animals and humans by measuring the appearance of fluoride metabolites (fluoride ion, nonvolatile organic fluoride, trifluoroacetic acid) in blood and urine. Desflurane administered to rats (either pretreated or not pretreated with phenobarbital or ethanol) for 3.2 MAC-hours and to swine for 5.5 MAC-hours produced fluoride ion levels in blood that were almost indistinguishable from values measured in control animals. In contrast, a significant 17% increase in plasma fluoride ion concentration in swine was detected 4 hr after exposure to desflurane. In human studies, desflurane administered to patients (3.1 MAC-hours) and volunteers (7.35 MAC-hours) resulted in postanesthesia serum fluoride in concentrations that did not differ from background fluoride ion concentrations. Similarly, postanesthetic urinary excretion of fluoride ion and organic fluoride in volunteers was comparable to preanesthetic excretion rates. Small but statistically significant levels of trifluoroacetic acid were found in both serum and urine from volunteers after exposure to desflurane. Peak serum concentrations averaging 0.38 +/- 0.17 uM trifluoroacetic acid (mean +/- SD) and peak urinary excretion rates averaging 0.169 +/- 0.107 umol/hr were detected in volunteers 24 hr after desflurane exposure. Although these increases in trifluoroacetic acid after exposure to desflurane were statistically significant, they are approximately 10-fold less than levels seen after exposure to isoflurane. Desflurane strongly resists biodegradation, and only a small amount is metabolized in animals and humans.

Minimally biotransformed in the liver in humans (approximately 0.02% of the quantity absorbed).

CRS35BZ94Q

DESFLURANE

Physiologic Effects [PE] - General Anesthesia

Established Pharmacologic Class [EPC] - General Anesthetic

Desflurane is a General Anesthetic. The physiologic effect of desflurane is by means of General Anesthesia.

DESFLURANE

Gases or volatile liquids that vary in the rate at which they induce anesthesia; potency; the degree of circulation, respiratory, or neuromuscular depression they produce; and analgesic effects. Inhalation anesthetics have advantages over intravenous agents in that the depth of anesthesia can be changed rapidly by altering the inhaled concentration. Because of their rapid elimination, any postoperative respiratory depression is of relatively short duration. (From AMA Drug Evaluations Annual, 1994, p173)

Data regarding the Cmax, Tmax, and AUC of desflurane are not readily available.

Initially, desflurane is rapidly eliminated from the lungs. A small amount of the metabolite trifluoroacetic acid is eliminated in the urine and only 0.02% of an inhaled dose is recovered as urinary metabolites.

Desflurane has a median volume of distribution of 612 mL/kg.

A 26 g dose of desflurane is 90% eliminated from the brain after 33 hours. The metabolite trifluoroacetic acid has a urinary clearance rate of 0.169 ± 0.107 µmol/L.

The concentrations of desflurane in milk are probably of no clinical importance 24 hours after anesthesia.

Due to the volatile nature of desflurane in plasma samples, the washin-washout profile of desflurane was used as a surrogate of plasma pharmacokinetics. Eight healthy male volunteers first breathed 70% N2O/30% O2 for 30 minutes and then a mixture of SUPRANE (desflurane, USP) 2.0%, isoflurane 0.4%, and halothane 0.2% for another 30 minutes. During this time, inspired and endtidal concentrations (FI and FA) were measured. The FA/FI (washin) value at 30 minutes for desflurane was 0.91, compared to 1.00 for N2O, 0.74 for isoflurane, and 0.58 for halothane. The washin rates for halothane and isoflurane were similar to literature values. The washin was faster for desflurane than for isoflurane and halothane at all time points. The FA/FAO (washout) value at 5 minutes was 0.12 for desflurane, 0.22 for isoflurane, and 0.25 for halothane. The washout for SUPRANE was more rapid than that for isoflurane and halothane at all elimination time points. By 5 days, the FA/FAO for desflurane is 1/20th of that for halothane or isoflurane.

MEDICATION

Use (kg) in Switzerland (2009): >2500

Used for maintenance of general anesthesia. Due to this airway irritability, Desflurane is infrequently used to induce anesthesia via inhalation techniques. [Wikipedia]

Preparation and use as anesthetic: R.C. Terrell, US 4762856 (1988 to BOC)

Prepared but not claimed: J.P. Russell, et al., US 3897502 (1975 to Airco)