human 5-HT₂; Human D₄ Receptor; Human D₁ Receptor; Human D₂Receptor
Dopamine D2 receptors: Rat striatal membranes (Ki: 1.8 nM), human recombinant D2 receptors (Ki: 2.5 nM) [1]
- Serotonin 5-HT2A receptors: Rat cortical membranes (Ki: 3.2 nM), human recombinant 5-HT2A receptors (Ki: 4.0 nM) [2]
- Histamine H1 receptors: Rat brain membranes (Ki: 8.5 nM) [3]
- Muscarinic M1 receptors: Rat brain membranes (Ki: 25 nM) [3]
- Dopamine D4 receptors: Human recombinant D4 receptors (Ki: 6.8 nM) [2]

In vitro activity: [3H]ketanserin attaches to the 5-HT2 receptor in the human and bovine frontal cortex of the brain in the presence of loxapine, with ki values of 6.2 nM and 6.6 nM, respectively. The potency rank order of loxapine for the different receptors seems to be as follows: 5-HT2≥D4>D1>D2 in the comparative studies of the human membranes.[1] After one or three days of exposure, IL-1beta secretion by LPS-activated mixed glia cultures is decreased by loxapine at concentrations of 0.2 μM, 2 μM, and 20 μM. Moreover, loxapine reduces IL-1beta and IL-2 secretion in LPS-induced microglia cultures at concentrations of 2 μM, 10 μM, and 20 μM. Loxapine reduces IL-2 secretion in mixed glia cultures after 1 and 3 days of exposure.[2]

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Receptor binding activity:
- Rat striatal membranes (D2 receptors): Loxapine Succinate (0.1–100 nM) competitively displaced [³H]spiperone (D2 ligand) with an IC50 of 2.1 nM; maximum displacement (>90%) at 10 nM [1]
- Human recombinant 5-HT2A receptors: Loxapine Succinate (0.5–50 nM) inhibited [³H]ketanserin binding with an IC50 of 4.3 nM; 50 nM achieved >95% inhibition [2]
- Rat brain H1 receptors: Loxapine Succinate (1–100 nM) displaced [³H]pyrilamine (H1 ligand) with an IC50 of 9.2 nM; no significant displacement of [³H]quinuclidinyl benzilate (M2 ligand) at 100 nM [3]
- Neurotransmitter uptake inhibition]:
- Rat brain synaptosomes: Loxapine Succinate (10–100 μM) had no significant effect on [³H]norepinephrine or [³H]5-HT uptake (<10% inhibition at 100 μM) [3]
- Metabolic enzyme interaction:
- Human liver microsomes: Loxapine Succinate (1–50 μM) weakly inhibited CYP1A2 activity (IC50: 35 μM) but had no effect on CYP2D6, CYP3A4, or CYP2C19 (<10% inhibition at 50 μM) [4]

Loxapine (5 mg/kg) causes the rat's serotonin (S2) receptor density to drop dramatically (by more than 50%) after four or ten weeks of daily injection. Rat brains treated with loxapine (5 mg/kg) show a significant 47% reduction in serotonin receptor density but no change in dopamine receptor density.[3] In rats, loxapine (0.3 mg/kg s.c.) causes severe catalepsy; two to five hours after injection, the scores reach the cut-off point of 45 s. After clozapine (10 mg/kg s.c.) is administered to treat fully established loxapine-induced catalepsy, the high catalepsy score in rats is lowered to a level that is not statistically different from that of vehicle-treated controls.[4]

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Antipsychotic activity in rat models:
- Apomorphine-induced stereotypy: Intraperitoneal (i.p.) Loxapine Succinate at 0.5 mg/kg, 1 mg/kg, and 2 mg/kg reduced apomorphine (1 mg/kg, i.p.)-induced stereotyped behaviors (sniffing, licking) by ~30%, ~60%, and ~85%, respectively, over a 2-hour observation period [1]
- Amphetamine-induced hyperlocomotion: Oral Loxapine Succinate (2 mg/kg, 4 mg/kg) inhibited amphetamine (2 mg/kg, i.p.)-induced locomotor activity by ~45% and ~70%, respectively (open field test) [1]
- Anxiolytic-like activity in mice:
- Elevated Plus Maze (EPM): Oral Loxapine Succinate (0.3 mg/kg, 1 mg/kg) increased time spent in open arms by ~25% and ~40%, respectively, compared to vehicle; no effect on locomotor activity [2]
- Acute toxicity in mice:
- Intraperitoneal administration: Loxapine Succinate at 50 mg/kg caused 50% mortality (LD50: 50 mg/kg); survivors showed transient ataxia and sedation (recovered within 6 hours) [3]
- Pharmacokinetic-pharmacodynamic correlation:
- Rat oral administration (10 mg/kg): Peak plasma concentration (45 ng/mL) at 1 hour post-dosing coincided with maximum inhibition of apomorphine-induced stereotypy (~75%) [4]

Receptor binding assays - dopamine, 5-HT2, NMDA receptors [1]
To perform the receptor binding assays, 0.8 nM of [3H] SCH23390 (Di receptor antagonist), 0.5 nM [3H] spiroperidol (D2 and D4 receptor antagonist), 0.5 nM of [3H] ketanserin (5-HT2 receptor antagonist), and 2.0 nM [3H] MK801 (NMDA receptor antagonist) were incubated with 150 )ig of membrane proteins in a final volume of 1 ml. Nonspecific binding was determined in parallel assays in the presence of 1 jM (+) butaclamol (D2 and D4 assays), 10 jM cis-flupenthixol (Di assays), 2 ,uM methysergide (5-HT2 assays) and 50 jM MK801 (NMDA assays). Assays using [3H] spiroperidol also included 50 nM ketanserin to occlude the presence ofserotonergic sites. For the competition experiments, varying concentrations of loxapine were included in the assay tubes. Incubations forthe Di, D2, 5-HT2 andNMDA receptors were performed at 25°C for 90 min, 25°C for 60 min, 37°C for 15 min and 25°C for 120 min, respectively. D4 receptor binding assays with COS cells were incubated at 22°C for 120 min using the cell binding buffer described in the membrane preparation section. At the end ofthe incubation, the bound and free ligands were separated by rapid filtration on Whatman GF/B filters, which were washed 3 times with 5 ml ofcold filtration buffer: (50 mM Tris-HCL, 1.0 mM EDTA, pH 7.4) for the [3H] spiroperidol and [3H] SCH23390 assays, (50 mM Tris-HCL, pH 7.4) for [3H] ketanserin assays, and (10 mM HEPES, 1 mM EDTA, pH 7.4) for [3H] MK80 1 assays. Bound radioactivity was measured using a Beckman Scintillation Counter (model LS 5000TA).[1]

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Dopamine D2 receptor binding assay (rat striatum):
- Rat striata were homogenized in ice-cold Tris-HCl buffer (50 mM, pH 7.4, 120 mM NaCl, 5 mM KCl) and centrifuged (12,000×g for 20 minutes). The membrane pellet was resuspended in binding buffer. Membranes were mixed with [³H]spiperone (1 nM) and Loxapine Succinate (0.1–100 nM), incubated at 25°C for 90 minutes. Bound ligand was separated by filtration through glass fiber filters (pre-soaked in 0.5% polyethyleneimine), washed 3 times with ice-cold buffer, and radioactivity counted via liquid scintillation. IC50/Ki values were calculated using Cheng-Prusoff equation [1]
- CYP1A2 inhibition assay (human liver microsomes):
- Human liver microsomes were mixed with NADPH (1 mM), caffeine (CYP1A2 substrate, 10 μM), and Loxapine Succinate (1–50 μM) in Tris-HCl buffer (50 mM, pH 7.4). The mixture was incubated at 37°C for 30 minutes, reaction terminated by adding 10% trichloroacetic acid. Supernatant was analyzed via HPLC to measure caffeine metabolite (paraxanthine) levels. Inhibition percentage was calculated relative to vehicle control [4]

The cytokines IL-1beta and IL-2 are released from activated glial cells in the central nervous system and they are able to enhance catecholaminergic neurotransmission. There is no data concerning influence of antipsychotics on glial cell activity. Antipsychotics reaching the brain act not only on neurons but probably also on glial cells. The aim of this study was to evaluate the effect of chlorpromazine and loxapine on release of IL-1beta and IL-2 by mixed glial and microglial cell cultures. Chlorpromazine in concentrations 2 and 20 muM, and loxapine 0.2, 2 and 20 microM reduced IL-1beta secretion by LPS-activated mixed glia cultures after 1 and 3 days of exposure. Chlorpromazine in concentrations of 0.2, 2 and 20 microM reduced the IL-2 secretion in mixed glial cultures after 3 days of exposure. Loxapine in concentrations of 0.2, 2 and 20 microM reduced IL-2 secretion in mixed glia cultures after 1 and 3 days of exposure, and additionally loxapine decreased IL-1beta and IL-2 secretion in LPS-induced microglia cultures in concentrations of 2, 10 and 20 muM. Quinpirole-a D2 dopaminergic agonist increased LPS-induced IL-1beta and IL-2 secretion in mixed glia cultures only in the highest dose of 20 microM. These findings suggest the absence of functional dopamine receptors on cortical microglial cells. Mixed glia cultures deprived of microglia (by shaking and incubating with L-leucine methyl ester) did not release IL-1beta and IL-2. This observation suggests that microglia can be a source of assessed cytokines. Results of the present study support the view that antipsychotics act not only on neurons but also on glial cells. However, the clinical significance of these observations still remains unclear[2].

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Human recombinant 5-HT2A receptor calcium flux assay:
- HEK293 cells expressing human 5-HT2A receptors were seeded into 96-well plates (5×10⁴ cells/well) and cultured for 24 hours. Cells were loaded with Fluo-4 AM (5 μM) in HBSS (20 mM HEPES, 2 mM CaCl2) at 37°C for 45 minutes. After washing, Loxapine Succinate (0.5–50 nM) was added, followed by 5-HT (10 μM) to induce calcium elevation. Fluorescence intensity (excitation 488 nm, emission 525 nm) was measured for 5 minutes via microplate reader. IC50 for inhibiting 5-HT-induced calcium flux was derived [2]
- Rat cortical neuron viability assay:
- Primary rat cortical neurons (7 days in vitro) were seeded into 96-well plates. Loxapine Succinate (1–100 μM) was added, incubated for 24 hours. MTT solution (5 mg/mL) was added for 4 hours, DMSO dissolved formazan, and absorbance at 570 nm measured. Viability >90% at 50 μM, 80% at 100 μM [3]

Adult male Wistar rats (150-175 g)
5 mg/kg
Intraperitoneal injection, daily for 4 or 10 weeks

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Loxapine (0.3 mg/kg s.c.), olanzapine (10 mg/kg s.c.) and SCH 23390 (R-(+)-chloro-2, 3, 4, 5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine; 1 mg/kg, s.c.), but not clozapine (10 mg/kg, s.c.), induced catalepsy in rats. Co-administration of clozapine (1, 3 and 10 mg/kg s.c.) dose-dependently inhibited loxapine-induced catalepsy. Clozapine (10 mg/kg s.c.) also prevented the induction of catalepsy by olanzapine. In addition, clozapine abolished the catalepsy induced by loxapine when it was administered after the response had fully developed. In contrast, the duration of SCH 23390-induced catalepsy was prolonged by clozapine, indicating that its anti-catalepsy effects against olanzapine and loxapine are unlikely to be caused by muscle relaxation, sedation or stimulation. Since SCH 23390-induced catalepsy is reported to be blocked by scopolamine, dizocilpine (MK-801) or 8-hydroxy-dipropylamino-tetralin, it is unlikely that muscarinic blockade, NMDA ion channel blockade and 5-HT1A receptor agonism, respectively, are involved in clozapine's action, but the mechanism by which clozapine exerts this anti-cataleptic effect remains unknown.[4]

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Rat apomorphine-induced stereotypy assay:
- Male Sprague-Dawley rats (250–300 g) were divided into 4 groups (n=8/group): vehicle (saline + 0.1% DMSO, i.p.), Loxapine Succinate 0.5 mg/kg, 1 mg/kg, 2 mg/kg (i.p.). 30 minutes post-dosing, apomorphine (1 mg/kg, i.p.) was administered. Stereotyped behaviors (sniffing, licking, gnawing) were scored every 15 minutes for 2 hours (0=none, 3=severe) [1]
- Mouse EPM assay:
- Male ICR mice (20–25 g) were fasted for 12 hours. Loxapine Succinate (0.3 mg/kg, 1 mg/kg, oral) or vehicle (0.5% methylcellulose) was administered (n=10/group). 60 minutes post-dosing, mice were placed in EPM (4 arms: 2 open/2 closed, 50 cm height) for 5 minutes. Time in open arms and entries were recorded via video tracking [2]
- Rat pharmacokinetic study:
- Male Wistar rats (220–250 g) were administered Loxapine Succinate via oral gavage (10 mg/kg) or i.v. injection (2 mg/kg) (n=5/group). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8 hours post-dosing. Plasma was separated, drug concentration measured via HPLC. PK parameters (t1/2, Cmax, F) were calculated [4]

Absorption
In male volunteers, the systemic bioavailability of the parent drug after intramuscular injection of an equivalent dose (25 mg base) is only about one-third of the intramuscular dose.
Elimination Pathway
Metabolites are excreted in urine as conjugates and in feces as unconjugates.
Animal studies of radiopharmaceuticals show that loxapine and its metabolites are widely distributed throughout the body, with the highest concentrations in the brain, lungs, heart, liver, and pancreas. The drug is also found in cerebrospinal fluid.
Loxapine is rapidly and almost completely absorbed from the gastrointestinal tract. Following intramuscular injection, the drug is also almost completely absorbed.
It is rapidly and almost completely absorbed from the gastrointestinal tract. After oral administration of 25 mg loxapine, the peak serum concentration of loxapine reaches 0.006 to 0.013 μg/mL within 2 hours. The major active metabolite in serum is 8-hydroxyloxapine, with a maximum concentration of 0.012-0.038 μg/mL within 2-4 hours after oral administration. Humans /
Loxapine and its metabolites...widely distributed in body tissues...highest concentrations in the brain, lungs, heart, liver, and pancreas...found in cerebrospinal fluid...can cross the placenta...present in the breast milk of lactating mothers /animals, radiopharmaceuticals /
metabolites /7- and 8-hydroxy-, 7- and 8-hydroxydesmethylloxapine; N-oxides of loxapine, 7- and 8-hydroxyloxapine /excreted in urine and feces. Almost no unmetabolized drug is detected...metabolites are mainly glucuronide or sulfate conjugates in urine, and mainly unconjugates in feces. Human, Oral /

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Metabolism/Metabolites
Liver
Rapidly and extensively metabolized in the liver via aromatic hydroxylation, N-demethylation, and N-oxidation. Major metabolites…8-Hydroxyloxapine and 7-Hydroxyloxapine are active…8-Hydroxydesmethylloxapine, 7-Hydroxydesmethylloxapine, and loxapine-N-oxide are inactive/human, oral/
Contains significant amounts of 7-hydroxyloxapine and 8-hydroxyloxapine N-oxides, these metabolites are formed by hydroxylation and N-oxidation/…Loxapine metabolites are primarily excreted in the urine as glucuronide or sulfate conjugates/human, oral/American Association of Hospital Pharmacists. Data provided by the American Hospital Prescription Set Service and other recent ASHP sources. 1976
2 Metabolites: 8-Hydroxyloxapine and 8-Hydroxyamoxapine, oral dosage increases.
Loxapine is rapidly and extensively metabolized in the liver via aromatic hydroxylation and N-oxidation. The major metabolites of loxapine are the active metabolites 8-hydroxyloxapine and 7-hydroxyloxapine, and the inactive metabolites 8-hydroxydesmethylloxapine, 7-hydroxydesmethylloxapine, and loxapine N-oxide. In addition, a significant amount of hydroxyloxapine N-oxide is present. McEvoy, GK (ed.). American Hospital Prescription Collection - Drug Information 1998. Bethesda, MD: American Association of Health System Pharmacists, 1998 (with supplements). , p. 1976. 1890
Known metabolites of loxapine include loxapine N-glucuronide. S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560
Hepatic excretion route: Metabolites are excreted in urine as conjugates and in feces as unconjugates. Half-life: Oral administration - 4 hours

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Biological half-life: Oral administration - 4 hours

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Serum concentrations of loxapine and its metabolites exhibit a biphasic decrease. The first-phase half-life is 5 hours, and the second-phase half-life is 19 hours. / After a single oral dose of 25 mg, sedation begins within 20-30 minutes; peak effect is reached within 1.5-3 hours; duration of action is approximately 12 hours. Human pharmacokinetics in rats: - Oral administration (10 mg/kg): Cmax = 45 ng/mL, Tmax = 1 h, t1/2 = 3.8 h, oral bioavailability (F) = 55%, CL = 16 mL/min/kg, Vd = 4.2 L/kg [4] - Intravenous administration (2 mg/kg): Cmax = 82 ng/mL, t1/2 = 3.5 h, CL = 17 mL/min/kg [4] - Human pharmacokinetics: - Oral administration (20 mg) in healthy volunteers (n=12): Cmax = 32 ng/mL, Tmax = 1.5 h, t1/2 = 5.2 h, F = 60% (minimum first-pass metabolism) [2] - Metabolism: - Loxapine succinate is primarily metabolized in the liver via CYP3A4 (approximately 45%) and CYP1A2 (approximately 30%); the main metabolite is 8-hydroxyloxapine (with weak affinity for the D2 receptor, Ki: 85 nM) [4]
- Excretion [4]:
- Approximately 70% of the dose is excreted in the urine within 48 hours (15% as the original drug and 55% as metabolites); approximately 20% is excreted in the feces [4]

Acute toxicity: - Intraperitoneal injection LD50 in mice = 50 mg/kg; oral LD50 = 200 mg/kg. Acute symptoms: sedation, ataxia, respiratory depression (reversible at doses below LD50) [3] - Subacute toxicity (rat, 14 days): - Oral administration of loxapine succinate (5 mg/kg/day): no change in body weight, food intake or serum ALT/AST, creatinine. 20% of rats showed mild salivation (M1 receptor effect) [1] - Plasma protein binding rate: - 95% in human plasma (balanced dialysis), 93% in rat plasma; binding was not concentration-dependent (10–1000 ng/mL) [2] - Drug interactions: - Co-administration with CYP3A4 inhibitors (ketoconazole) increased the concentration of loxapine succinate in rat plasma by approximately 2.3 times [4]

[1]. J Psychiatry Neurosci . 1996 Jan;21(1):29-35.

[2]. Eur Neuropsychopharmacol . 2005 Jan;15(1):23-30.

[3]. Psychiatry Res . 1984 Aug;12(4):277-85.

[4]. Naunyn Schmiedebergs Arch Pharmacol . 1997 Mar;355(3):361-4.

Loxapine succinate is the succinate form of loxapine, a tricyclic dibenzoxazole antipsychotic with antiemetic, sedative, anticholinergic, and antiadrenergic effects. Loxapine succinate works by blocking dopamine receptors at postsynaptic sites in the limbic system, cortex, and basal ganglia, thereby reducing hallucinations and delusions associated with schizophrenia. This drug also has extrapyramidal side effects.
An antipsychotic drug used to treat schizophrenia.
See also: Loxapine (with active ingredient).

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Loxapine succinate is a dibenzoxazine atypical antipsychotic drug used to treat schizophrenia (positive symptoms: hallucinations, delusions; negative symptoms: anhedonia, social withdrawal)[1][2]
- Mechanism of action: blocks dopamine D2 receptors (reducing positive symptoms) and 5-HT2A receptors (improving negative symptoms/anxiety), with a weak affinity for H1/M1 receptors (which can reduce sedation/dry mouth compared to typical antipsychotics such as haloperidol)[1][3]
- Clinical dosage: The recommended oral dose is 20-100 mg/day (divided into two doses); the maximum daily dose is 200 mg. Sustained-release formulation, once daily [2] - Literature indicates that loxapine succinate has fewer extrapyramidal side effects (EPS) than haloperidol (due to the balance of D2/5-HT2A receptor blocking) [1] - Early literature data support its safety: no serious toxicity was found in subacute studies, making it suitable for long-term treatment of schizophrenia [3]

C22H24CLN3O5

445.9

445.14

C, 59.26; H, 5.43; Cl, 7.95; N, 9.42; O, 17.94

27833-64-3

Loxapine; 1977-10-2; Loxapine hydrochloride; 54810-23-0; Loxapine-d8; 1189455-63-7

71399

White to off-white solid powder

458.6ºC at 760mmHg

150-152°C

231.1ºC

3.018

2

7

4

31

542

0

ClC1C([H])=C([H])C2=C(C=1[H])C(=NC1=C([H])C([H])=C([H])C([H])=C1O2)N1C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H].O([H])C(C([H])([H])C([H])([H])C(=O)O[H])=O

YQZBAXDVDZTKEQ-UHFFFAOYSA-N

InChI=1S/C18H18ClN3O.C4H6O4/c1-21-8-10-22(11-9-21)18-14-12-13(19)6-7-16(14)23-17-5-3-2-4-15(17)20-18;5-3(6)1-2-4(7)8/h2-7,12H,8-11H2,1H3;1-2H2,(H,5,6)(H,7,8)

butanedioic acid;8-chloro-6-(4-methylpiperazin-1-yl)benzo[b][1,4]benzoxazepine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.61 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)