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Abstract

The aim of the present study was to evaluate the anti-inflammatory effect of fluoxetine in carrageenan- and lipoplysaccharide-induced models of inflammation by investigating the changes in serum levels of pro-inflammatory cytokine TNF-α and anti-inflammatory cytokines IL-10 and TGF-β after single and repeated administration of the drug. To study the effect of a single and repeated dose fluoxetine on carrageenan-induced paw edema male Wistar rats were divided into five groups (n = 8): control group; positive control group; and three experimental groups treated with 5, 10, and 20 mg/kg bodyweight (bw) fluoxetine, respectively. To study the effect of a single and repeated dose of fluoxetine on serum cytokine levels, the animals were divided in four groups (n = 8): two control groups treated with saline and two experimental groups treated with fluoxetine 20 mg/kg bw. Carrageenan and LPS were injected immediately after fluoxetine or saline injection. Serum cytokine concentrations were tested by enzyme immunoassay. In single administration only the highest dose used inhibited carrageenan-induced inflammation. Edema inhibition was seen with 10 and 20 mg/kg bw fluoxetine after repeated administration. At 24 h a statistically significant effect on inhibition of carrageenan edema was found only in rats treated with 20 mg/kg bw fluoxetine In carrageenan-induced inflammation, fluoxetine significantly increased Il-10 and decreased TNF-α after repeated administration. Surprisingly, in single-dose treated animals an increase in TNF-α values upon fluoxetine administration was observed in this model of inflammation. In LPS-induced inflammation, fluoxetine significantly decreased TNF-α after single and repeated treatment. Fluoxetine has anti-inflammatory and immunomodulatory effect in the carrageenan-induced model of exudative inflammation. In LPS-induced inflammation it showed an immunomodulatory effect manifested with a decrease in pro-inflammatory cytokine TNF-α.

Keywords

carrageenan cytokines fluoxetine inflammation lipopolysaccharide

Introduction

Growing evidence suggests that immune dysregulation and inflammation may play a role in the pathophysiology of depressive disorders. According to the cytokine hypothesis, depressive disorders are related to increased production of cytokines, including interleukins, tumor necrosis factor alfa (TNF-α), and interferon-α and –γ.¹ A meta-analysis of cytokines in major depression shows higher concentrations of pro-inflammatory cytokines IL-6 and TNF-α in depressed patients compared with control subjects.²

Fluoxetine is an antidepressant from the group of selective serotonin reuptake inhibitors (SSRI). It blocks serotonin transporter protein by high-affinity mechanism and increases the concentration of this mediator in the central nervous system (CNS) and peripheral tissues.³

Experimental data showed that along with its main pharmacological effect – antidepressive – fluoxetine has ant-inflammatory activity.⁴ Studies on the anti-inflammatory activity of antidepressants are of interest in several areas. Based on the cytokine theory it may be assumed that the efficacy of antidepressants in the treatment of depressive disorders may at least partly be due to decreased synthesis of pro-inflammatory cytokines.⁵ In patients with treatment-resistant depression there are elevated cytokine levels although the treatment, which also implies a link between depression, antidepressants, and immune system.⁶ Depressive symptoms induced by interferon α in people may be affected by treatment with the SSRI antidepressant paroxetine.⁷

On the other hand, the anti-inflammatory effect of antidepressants may be useful in the treatment of inflammatory diseases that accompany depression or antidepressants can be used alone for this purpose. For example there is clinical evidence that some antidepressants, such as bupropion, can induce remission in Crohn’s disease, psoriasis, and atopic dermatitis.^8,9

Fluoxetine has anti-inflammatory activity in an experimental model of inflammation with carrageenan.⁴ In the formalin model of inflammation, however, this effect is not observed.¹⁰ Roumestan et al. have shown that in a model of lipopolysaccharide-induced sepsis in mice fluoxetine reduces mortality and decreases the level of TNF-α, when applied preventively. They have also found that fluoxetine reduces pulmonary inflammation in rats sensitized with ovalbumin, resulting in a reduced number of macrophages, lymphocytes, eosinophils, and neutrophils, and decreased expression of nuclear factor NF-κB.¹¹ In experimental autoimmune encephalomyelitis prior treatment of the rats with fluoxetine reduces the number of inflammatory foci, demyelination, and serum levels of interferon-gamma.¹² In in vitro experiments, it was found that fluoxetine has a protective effect against neurodegeneration induced by bacterial lipopolysaccharide (LPS) and the neurotoxin 1-methyl-4-phenylpyridine. The authors concluded that this is due to its ability to reduce the release of a number of pro-inflammatory and cytotoxic factors such as TNF-α, IL-1ß, nitric oxide, and reactive oxygen radicals, as well as inhibition of microglial NF-κB.¹³ It was suggested that fluoxetine inhibits the mRNA for these cytokines (as well as for IL-6) by inhibiting the phosphorylation and nuclear translocation of the p65 subunit of NF-κB, and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in the LPS-stimulated microglia.¹⁴ In experiments with human synovial cells, it was found that fluoxetine causes inhibition of the synthesis of hyaluronic acid, prostaglandin E2, and nitric oxide.¹⁵

IL-10 is a key regulator of depression symptoms and modulates depressive-like behavior.¹⁶ In vitro studies have shown that various antidepressants such as tricyclic (imipramine, clomipramine), SSRI (citalopram, fluoxetine, sertraline), SNRI (selective norepinephrine reuptake inhibitors) – venlafaxine, heterocyclic (trazodone) monoamine oxidase A inhibitors (moclobemide) significantly reduced the INF γ / IL-10 ratio. This raises the question for common effect of these drugs on inflammatory response, namely increased production of anti-inflammatory cytokine IL-10.^17,18 Therefore the effect of fluoxetine on serum levels of this cytokine may contribute to its therapeutic effect in major depressive disorders.

Carrageenan-induced paw edema is a well-known model of inflammation for evaluation of anti-inflammatory activity of antidepressants. The carrageenan edema is characterized by distinct phases with the involvement of different mediators. Release of nitric oxide and pro-inflammatory cytokines such as TNF-α and IL-1β are also involved in the delayed phase of carrageenan edema.¹⁹

Lipopolysaccharide from the E. coli cell wall is one of the most potent stimuli for cytokine release and is used as an experimental model for study the effects of antidepressants on the cytokine production.

The aim of the present study was to evaluate the anti-inflammatory effect of fluoxetine in carrageenan- and lipopolysaccharide-induced models of inflammation by investigating the changes in serum levels of pro-inflammatory cytokine TNF-α and anti-inflammatory cytokines IL-10 and TGF-β (transforming growth factor beta) after single and repeated administration of the drug.

Material and methods

Animals

The design of the experiment was approved by the Bulgarian Food Safety Agency (license no. 21 of 19 March 2012) and by the ethics Committee at the Medical University of Plovdiv (protocol no. 4 of 19 June 2013). Male Wistar rats with an average weight of 220–250 g were used. Animals were housed under standard laboratory conditions: 12:12 h light/dark cycle, room temperature 26.5 ± 1°C, and free access to food and water. Experiments were performed between 08:00 and 15:00.

Chemicals

Λ-carrageenan (Sigma), Fluoxetine hydrochloride (Sigma), Diclofenac sodium (Hexal), and Lipopolysaccharide from E. coli O55 (Sigma) were used. Carrageenan was dissolved in isotonic saline and 1% solution was used. TGF-1β, IL-10, and TNF-α Platinum ELISA kits (Bioscience) for rats were used for measurement of serum cytokine levels.

Carrageenan-induced paw edema

Paw edema was induced by injecting 100 µL of a 1% solution of Λ-carrageenan in saline into the right hind paw of the rat. Hind paw volume was measured immediately before carrageenan injection and at 2 h, 3 h, 4 h, and 24 h thereafter with a pletismometer (Ugo Basile, Italy).

Lipopolysaccharide (LPS)-induced inflammation

LPS was dissolved in isotonic saline and was injected intraperitoneally in dose 250 μg/kg bw 4 h before blood collection.

Experimental design

In the first series of experiments, the effect of a single-dose i.p. fluoxetine on carrageenan-induced paw edema was studied. Animals were divided into five groups (n = 8). The control group received only saline, the positive control group was treated with diclofenac sodium 25 mg/kg bw, and the three experimental groups were treated with 5, 10, and 20 mg/kg bw clomipramin. Paw volume was measured prior to carrageenan injection and at 2 h, 3 h, 4 h, and 24 h after that to determine the difference in paw volume.

In the second series of experiments, the effect of repeated doses i.p. fluoxetine on carrageenan-induced paw edema was studied. The experimental animals, the control, and positive control groups were treated as previously described in the first series of experiments but the treatment lasted 14 days and carrageenan edema was induced on day 15. Paw volume was measured as described in the first series of experiments.

In the third series of experiments, the effect of a single-dose i.p. fluoxetine on serum cytokine levels was studied. Animals were divided into four groups: two control groups (n = 8) treated with saline and two experimental groups (n = 8) treated with fluoxetine 20 mg/kg bw. Carrageenan and LPS were injected immediately after fluoxetine or saline injection and blood samples were collected 4 h thereafter.

In the fourth series of experiments, the effect of repeated doses i.p. fluoxetine on serum cytokine levels was studied. Animals were divided into four groups as described in the third series of experiments but were treated for 14 days. Carrageenan and LPS were injected on day 15 immediately after fluoxetine or saline injection and blood samples were collected 4 h thereafter.

Measurement of serum cytokine levels

TGF-1β, IL-10, and TNF-α concentrations were measured in diluted serum samples from rats collected 4 h after carrageenan and LPS injection using solid-phase ELISA. Assays were performed according to the manufacturer’s instructions. Absorbance was read at 450 and 620 nm using an ELISA reader. Absorbance was then recalculated as a concentration (pg/mL) using a standard curve. The detection limits of the assays employed were as follows: TGF-1β, 8 pg/mL; IL-10, 1.5 pg/mL, and TNF-α, 11 pg/mL. Intra-assay and inter-assay reproducibility varied as follows: for TGF-1β <3.7% and <8.6%; for IL-10 <5% and <10%, for TNF-α <5% and <10%.

Statistical analysis

Data were analyzed using the Independent Samples Т test from the software product SPSS 11.0. Mean values (X) ± SEM were calculated. Results were considered significant at P <0.05.

Results

Effect of acute administration of fluoxetine on carrageenan-induced paw edema

Fluoxetine at dose 5 mg/kg bw and 10 mg/kg bw i.p. did not show significant anti-inflammatory effect when compared with the control. The highest dose used caused significant inhibition in the development of paw edema at 2 h, 4 h, and 24 h (P = 0.04; P = 0.011, P <0.0001) as compared to the control group. The reference drug diclofenac caused significant inhibition of edema at 2 h, 3 h, and 4 h (P = 0.043; P = 0.022, and P = 0.006) post carrageenan challenge (Figure 1).

Figure 1.

Anti-inflammatory effect of fluoxetine in carrageenan-induced paw edema after single administration. *P <0.05 compared with saline at 2 h; **P <0.05 compared with saline at 3 h; ***P <0.05 compared with saline at 4 h; + P <0.05 compared with saline at 24 h.

Effect of repeated administration of fluoxetine on carrageenan-induced paw edema

The three used doses of fluoxetine significantly inhibited carrageenan edema at 2 h (P = 0.033; P <0.0001 and <0.0001, respectively) in comparison with the control. At 3 h this effect was absent in the group treated with 5 mg/kg bw fluoxetine, but was retained in the other two groups (P <0.0001). Significant anti-inflammatory effect at 4 h was observed only in the groups treated with 10 mg/kg bw (P <0.0001) and 20 mg/kg bw fluoxetine (P <0.0001). At 24 h, a statistically significant effect on inhibition of carrageenan edema was found only in rats treated with 20 mg/kg bw fluoxetine (P = 0.011). The reference drug diclofenac caused significant inhibition of edema at all tested hours (P = 0.004; P = 0.002; P <0.0001 and P <0.0001) (Figure 2).

Figure 2.

Anti-inflammatory effect of fluoxetine in carrageenan-induced paw edema after repeated administration. *P <0.05 compared with saline at 2 h; **P <0.05 compared with saline at 3 h; ***P <0.05 compared with saline at 4 h; + P <0.05 compared with saline at 24 h.

Effect of fluoxetine on the serum levels of anti-inflammatory cytokines TGF-1β and IL-10

In carrageenan-induced inflammation, single and repeated i.p. administration of fluoxetine at a dose of 20 mg/kg bw did not significantly change serum levels of TGF-1β when compared with the control group. In animals treated with single-dose fluoxetine, a statistically significant difference in the serum levels of IL-10 in comparison with the control was not found. In long-time treated rats fluoxetine significantly increased the level of IL-10 in the carrageenan model of inflammation (Figure 3).

Figure 3.

Effect of repeated fluoxetine treatment on serum levels of TGF-1β (a), Il-10 (b), and TNF-α (c) in rats with carrageenan model of inflammation. *P <0.05 compared with saline.

In LPS-induced inflammation fluoxetine non-significantly increased serum levels of TGF-1β after single and repeated administration. In this inflammatory model fluoxetine did not significantly change the levels of IL-10 (Figures 4 and 5).

Figure 4.

Effect of single-dose fluoxetine treatment on serum levels of TGF-1β (a), Il-10 (b), and TNF-α(c) in rats challenged with LPS. *P <0.05 compared with saline.

Figure 5.

Effect of repeated fluoxetine treatment on serum levels of TGF-1β (a), Il-10 (b), and TNF-α (c) in rats challenged with LPS. *P <0.05 compared with saline.

Effect of fluoxetine on the serum levels of pro-inflammatory cytokine TNF-α

LPS increased the TNF-α levels in control rats. Levels of TNF-α in single-dose rats and rats pretreated for 2 weeks with 20 mg/kg bw fluoxetine were significantly reduced in comparison with those of saline-treated animals after the LPS challenge (Figures 4 and 5). In carrageenan-induced inflammation fluoxetine significantly increased serum TNF-α levels after single administration (P <0.001) (Table 1) and decreased them after repeated treatment (P <0.05) (Figure 3).

Table 1.

Effect of single-dose fluoxetine treatment on serum levels of TNF-α in the carrageenan model of inflammation.

Groups	n	X ± SEM	t	P
Control	8	0	4.97	0.001
Fluoxetine 20 mg/kg bw	8	35.67 ± 7.18	4.97	0.001

Discussion

The major finding of this study is that fluoxetine has anti-inflammatory activity in carrageenan-induced inflammation after single and repeated administration and that it decreases serum levels of pro-inflammatory cytokine TNF-α after LPS challenge and increases anti-inflammatory cytokine IL-10 in the carrageenan model of inflammation after repeated administration.

In the carrageenan model of inflammation fluoxetine in a dose of 20 mg/kg showed significant anti-inflammatory effects in single-dose treated animals. This effect was observed in the first 4 h, and at 24 h. In multiple-dose treated animals and in the dose of 10 mg/kg bw the anti-inflammatory effect was found. Our results confirmed those of Abdel-Salam et al. for anti-inflammatory activity of fluoxetine in this experimental model.^4,20 In addition we have identified anti-inflammatory activity, and at 24 h, which in long-term treated animals was statistically significant only at the dose of 20 mg/kg bw. The intimate mechanism of this effect is not fully understood. Serotonin mediates anti-inflammatory activity in CNS. In experimental conditions an intracerebroventricular injection of exogenic 5-HT on rats with normal serotonin levels reduces carrageenan edema.²¹ Serotonin-releasing substances like amphetamine suppress immune functions.²² The anti-inflammatory effect of serotonin in CNS can be explained with its neuroendocrine action. In situ hybridization on rat brain slices with oligopeptides showed an increase of corticotropin-releasing hormone mRNA in the paraventricular nucleus and proopiomelanocortin in the anterior pituitary lobe upon stimulation of 5-HT receptors.²³ It can be suggested that the anti-inflammatory effect of fluoxetine is due to depletion of intracellular 5-HT, and increased extracellular 5-HT levels in the CNS.

IL-10 is one of the most important anti-inflammatory cytokines. It is a key regulator of depressive symptoms.¹⁶ In mice with knock out of the gene for IL-10 was observed depression similar state in experimental behavioral tests. In contrast the overexpression of the gene for this cytokine causes antidepressive effect.²⁴ It is assumed that the role of IL-10 in the pathogenesis of depression is due to its ability to inhibit the synthesis of pro-inflammatory cytokines. IL-10 inhibits the production of pro-inflammatory cytokines, such as TNFα, Il-6, and interferon-γ.²⁵ Antidepressants of different groups are able to affect serum level of IL-10. In in vitro conditions, co-incubation of whole human blood with a SSRI (fluoxetine, sertraline), SNRI (venlafaxine), tricyclic antidepressants (clomipramine, imipramine), reversible monoamine oxidase A inhibitor moclobemide, and 5-hydroxytryptophan, a precursor of serotonin, decreased production of interferon gamma and increased of IL-10 by peripheral immunocytes are observed.¹⁷ Ohgi et al. found that in mice, 5-hydroxytriptamine (a precursor of serotonin) and SSRI antidepressants (fluoxetine and paroxetine) stimulate the production of IL-10 in LPS-induced inflammation after single administration.²⁶ In the present study, in an LPS-induced model of inflammation, fluoxetine increases serum levels of IL-10 after both single and repeated administration but the results did not have statistical significance. This may be due to the limited number of samples and the large degree of inter-individual variability.

Fluoxetine significantly increased serum levels of IL-10 only in long-term treated animals with the carrageenan model of inflammation, suggesting the presence of this effect in the absence of systemic stimulation. Kubera et al. also found that the immunomodulatory effect of fluoxetine and other SSRI in mice depends on the duration of treatment.²⁷

In a meta-analysis on serum levels of pro- and anti-inflammatory cytokines in depressive disorders, Dowlati et al. found that pro-inflammatory cytokines TNF-α and Il-6 are elevated in depressed patients compared to the healthy controls.² Treatment with antidepressants of the group of SSRI significantly reduces serum TNF-α levels in depressive patients.^28,29 Experimental data on the effects of antidepressants on serum levels of TNF-α are contradictory. Kubera et al., in in vitro experiments with whole blood stimulated with phytohemagglutinin and LPS, found that serotonin, fluoxetine, imipramine, and venlafaxine stimulate the production of Il-6 and do not inhibit that of TNF-α.³⁰ In in vivo studies in rats by Yirmiya et al., it was found that desipramine and fluoxetine did not affect the LPS-induced increase in the expression of mRNA for IL-1β and TNF-α in the spleen.³¹ Other authors found a strong decrease in the values of TNF-α in LPS-stimulated whole blood incubated with clomipramine, imipramine, and sertraline.³² Our results show a statistically significant reduction in serum levels of TNF-α in LPS-induced inflammation, both after single and repeated treatment with fluoxetine. These data confirm those of Ohgi et al. for suppressive action of fluoxetine on the production of TNF-α after single administration in rats.²⁶ In other in vivo studies, the tricyclic antidepressant desipramine also inhibits the production of pro-inflammatory cytokines IL-1β and TNF-α and promotes IL-10 secretion after stimulation of olfactory bulbektomized rats.³³

Inhibition of serotonin reuptake and increased extracellular serotonin levels are probably related to the effect of fluoxetine on the production of TNFα. Serotonin and noradrenaline transporters are expressed not only in the CNS but also in peripheral blood mononuclear cells.^34,35 Furthermore, serotonin and noradrenaline are released from the lymphocytes and monocytes³⁵ and may induce immune modulation through receptors expressed on immune cells.³⁶ Pharmacological blockade of monoamine transporters could affect immune function by increasing the local concentration of serotonin and noradrenaline in the area of immune cells. Fluoxetine inhibits peripheral serotonin transporters and increases plasma serotonin levels in acutely treated rats.³⁷ 5-HT₄ and 5-HT₇ serotonin receptors are expressed on monocytes and their stimulation reduces secretion of LPS-induced release of TNF-α.³⁸ In experiments with mice, serotonin also increases the serum levels of IL-10.²⁶ Although the fact that IL-10 inhibits the secretion of TNF-α the results of our study do not support the idea that low serum levels of TNF-α are a consequence of elevated IL-10 levels.

After repeated administration of fluoxetine in rats, there was no increase in plasma serotonin levels observed.³⁷ The effect of this antidepressant on serum TNF-α in this case cannot be explained by its serotonergic mechanism of action. In vitro studies show that fluoxetine inhibits the production of TNF-α in microglial cell cultures. This effect is due to inhibition of the transcription factor NF-κB and its signaling pathway and inhibition of the phosphorylation of p38 MAPK.^13,14 We can assume that the effect of fluoxetine on TNF-α production after repeated administration is due to similar mechanisms in the periphery. Cytokine production is also dependent at least partly on TLR (toll-like receptor),³⁹ such as TLR 8 which plays an important role in the production of TNF-α. In an experimental study, Sacre et al. found that fluoxetine reduces the spontaneous production of TNF-α and IL-6 in synovial cell lines, as well as the activity of endosomal TLR (TLR 3, 7, 8, and 9).⁴⁰ Interestingly in the mentioned study, serotonin itself did not affect cytokine production, suggesting that the effect of the SSRI is not due to their main pharmacological activity of increasing serotonin levels.

There are relationships between peripheral and CNS inflammation.⁴¹ Peripheral administration of LPS through pro-inflammatory cytokines stimulates indolamine-2,3-dioxygenase and induces depressive-like behavior.⁴² We can speculate that changes in the level of TNF-α induced by fluoxetine may contribute to its therapeutic effect in depression.

In the carrageenan model of inflammation, an increase in serum levels of TNF-α in the saline group was observed only in experiments with repeated administration, while in an acute trial its level in the control group remained at zero. Surprisingly, fluoxetine increased the concentration of TNF-α after a single application in this model of inflammation. In experiments with cell cultures from the smooth muscle of the aorta, Yu et al. found that serotonin inhibits production of TNF-α by interaction with 5-HT_2A receptors.⁴³ In carrageenan inflammation increased expression of these receptors is observed. Since fluoxetine slightly antagonizes these receptors, it is possible that the observed increase in TNF-α is due to interaction of serotonin with 5-HT_2A receptor subtype. The data in the present study do not allow an explanation of the transitory rise in serum TNF-α by fluoxetine. In the carrageenan model of inflammation, the anti-inflammatory effect of this antidepressant was found after a single application, in spite of elevated TNF-α levels.

In the present study fluoxetine stimulates the production of TGF-ß in LPS-induced inflammation, although the results did not reach statistical significance. In clinical trials low serum levels of this cytokine were observed in patients with depression.^29,44 Myint et al. established an imbalance between Th1 and Th2 immune response in patients with depression, with elevated ratio interferon gamma / IL-4 and interferon gamma / TGF-1ß. Treatment with antidepressants alter this imbalance by affecting serum levels of TGF-1ß.⁴⁵ On other hand, in vitro experiments with whole blood from patients with depression showed increased levels of TGF-1ß.⁴⁶ After in vitro stimulation of peripheral monocytes from healthy volunteers with phytohemagglutinin and LPS, Szuster-Ciesielska et al. found that antidepressants imipramine and maprotiline significantly increased levels of TGF-1ß.⁴⁷ Our experimental results show the ability of fluoxetine to stimulate the production of TGF-ß in in vivo conditions. Since this cytokine has suppressive action on cell and humoral immunity we can speculate that fluoxetine affects pro- and anti-inflammatory cytokine balance by increasing the values of TGF-1ß. In the carrageenan model of inflammation significant changes in the values of TGF-1ß were not found after single and repeated treatment with fluoxetine. LPS-induced inflammation is probably a more appropriate model to study the influence of antidepressants on the production of TGF-1ß in the peripheral tissues.

In conclusion, the results of our study indicate that fluoxetine has anti-inflammatory and immunomodulatory effects in the carrageenan-induced model of exudative inflammation. In LPS-induced inflammation, it showed immunomodulatory effect manifested with a decrease in pro-inflammatory cytokine TNF-α.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Study on anti-inflammatory and immunomodulatory effects of fluoxetine in rat models of inflammation

Abstract

Keywords

Introduction

Material and methods

Animals

Chemicals

Carrageenan-induced paw edema

Lipopolysaccharide (LPS)-induced inflammation

Experimental design

Measurement of serum cytokine levels

Statistical analysis

Results

Effect of acute administration of fluoxetine on carrageenan-induced paw edema

Effect of repeated administration of fluoxetine on carrageenan-induced paw edema

Effect of fluoxetine on the serum levels of anti-inflammatory cytokines TGF-1β and IL-10

Effect of fluoxetine on the serum levels of pro-inflammatory cytokine TNF-α

Discussion

Footnotes

Declaration of conflicting interests

Funding

References