Vasoactive Intestinal Peptide (VIP)

1. Overview

Vasoactive intestinal peptide (VIP) is a 28-amino-acid neuropeptide belonging to the glucagon/secretin superfamily, first isolated from porcine duodenal extracts by Sami Said and Viktor Mutt in 1970 [1]. Originally characterized for its potent vasodilatory activity, VIP has since emerged as one of the most versatile signaling molecules in mammalian physiology, with established roles in vasodilation, smooth muscle relaxation, exocrine and endocrine secretion, immune modulation, neuroprotection, and circadian rhythm regulation [3][7][11].

The mature peptide has the sequence HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2, a molecular weight of 3326.8 Da, and a characteristic amidated C-terminus essential for biological activity. VIP adopts an alpha-helical conformation from approximately Val-3 to Asn-24, flanked by disordered N- and C-terminal regions. It is encoded by the VIP gene on chromosome 6q25.2 as part of a prepro-VIP precursor of 170 amino acids that also yields PHM-27 (peptide histidine methionine) in humans [3][21].

VIP signals primarily through two class B G protein-coupled receptors: VPAC1 and VPAC2, both binding VIP with nanomolar affinity (Kd approximately 1 nM). These receptors couple predominantly to Gs proteins, activating adenylyl cyclase and raising intracellular cAMP, which in turn activates protein kinase A (PKA) and exchange proteins activated by cAMP (Epac). VIP also binds the PAC1 receptor with much lower affinity (Kd >500 nM), distinguishing it from the closely related pituitary adenylate cyclase-activating polypeptide (PACAP), which binds all three receptors with high affinity [4][5][6].

The clinical significance of VIP extends across multiple therapeutic areas. Its synthetic form, aviptadil (marketed under the name Zyesami), holds FDA orphan drug designation for acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension (PAH), and received FDA fast track designation for COVID-19-associated respiratory failure [14][23]. VIP's broad immunomodulatory properties -- including Th2 skewing, regulatory T cell induction, and macrophage deactivation -- have made it one of the most intensively studied endogenous anti-inflammatory peptides in immunology [7][10][16].

Molecular Weight

3326.8 Da

Sequence

HSDAVFTDNYTRLRKQMAVKKYLNSILN-NH2 (28 aa)

Peptide Length

28 amino acids

Molecular Formula

C147H237N43O43S

Gene

VIP (6q25.2); prepro-VIP also encodes PHM-27

Primary Receptors

VPAC1 (Kd ~1 nM), VPAC2 (Kd ~1 nM); low affinity at PAC1 (Kd >500 nM)

Discovery

Said & Mutt, 1970 (porcine duodenal extracts)

Plasma Half-Life

~1-2 minutes (rapid peptidase degradation)

Synthetic Analog

Aviptadil (Zyesami) - FDA orphan drug for ARDS and pulmonary hypertension

2. Discovery and Historical Context

The discovery of VIP arose from an unexpected observation. In the late 1960s, Sami I. Said at the Medical College of Virginia found that systemic injection of mammalian lung extracts produced profound vasodilation and hypotension, suggesting the presence of an unknown vasoactive substance [3]. Seeking a more practical source of tissue for purification, Said partnered with Viktor Mutt at the Karolinska Institute in Stockholm -- the same laboratory where Mutt had previously helped isolate secretin and cholecystokinin.

Turning to porcine duodenal extracts, which were available in larger quantities, Said and Mutt isolated a peptide fraction with potent vasodilatory activity and published their landmark discovery in Science in 1970 [1]. They named the new molecule "vasoactive intestinal polypeptide" for its origin and its most prominent biological action. Subsequent sequencing revealed a 28-amino-acid peptide with structural homology to secretin, glucagon, and gastric inhibitory peptide, placing it within what is now recognized as the glucagon/secretin superfamily [3].

A pivotal advance came in 1976, when Said and Rosenberg demonstrated that VIP was abundantly expressed in the brain and peripheral nerves, transforming its classification from a gut hormone to a neuropeptide with dual peripheral and central distribution [2]. This discovery opened vast new avenues of investigation, revealing VIP's roles as a neurotransmitter and neuromodulator in the enteric nervous system, parasympathetic neurons, and specific populations of cortical interneurons.

The cloning of VPAC1 (1992) and VPAC2 (1994) receptors provided the molecular tools needed to dissect VIP signaling pathways. The development of aviptadil (synthetic VIP) for clinical applications, and the seminal work of Mario Delgado and Doina Ganea beginning in the late 1990s on VIP immunobiology, established VIP as a leading candidate for neuropeptide-based immunotherapy [7][8][9].

3. Molecular Biology and Gene Expression

Gene Structure and Processing

The human VIP gene is located on chromosome 6q25.2 and spans approximately 9 kilobases, containing seven exons separated by six introns that divide the gene into functional domains [21]. The gene encodes a 170-amino-acid preproprotein (prepro-VIP) that includes a signal peptide of approximately 20 amino acids, the PHM-27 peptide (peptide histidine methionine-27, the human homologue of porcine PHI), and VIP itself. Both PHM-27 and VIP are flanked by dibasic cleavage sites and require post-translational processing by prohormone convertases, followed by C-terminal amidation by peptidylglycine alpha-amidating monooxygenase (PAM) [3][21].

Tissue Distribution

VIP is widely expressed throughout the central and peripheral nervous systems. In the CNS, VIP-expressing neurons are found in the cerebral cortex (where VIP marks a distinct class of GABAergic interneurons), hippocampus, hypothalamus (particularly the suprachiasmatic nucleus), amygdala, and thalamus [11][12]. In the peripheral nervous system, VIP is a major neurotransmitter of parasympathetic and non-adrenergic, non-cholinergic (NANC) neurons innervating smooth muscle, exocrine glands, and blood vessels throughout the respiratory, gastrointestinal, and urogenital tracts [21].

Importantly, VIP is also expressed by immune cells. CD4+ and CD8+ T lymphocytes produce and secrete VIP, with the highest production by Th2 and T2 CD8+ cells. This endogenous immune cell production provides an autocrine/paracrine anti-inflammatory signal within the immune microenvironment [16].

Superfamily Relationships

VIP belongs to a family of structurally related peptides that includes secretin, glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), gastric inhibitory peptide (GIP), growth hormone-releasing hormone (GHRH), pituitary adenylate cyclase-activating polypeptide (PACAP), and helodermin. These peptides share sequence homology, alpha-helical secondary structure, and signaling through class B (secretin family) GPCRs [4][5].

4. Mechanism of Action

Receptor Pharmacology

VIP exerts its biological effects through two primary receptors, VPAC1 and VPAC2, with distinct tissue distribution patterns and signaling characteristics [5][6]:

VPAC1 is constitutively expressed on T lymphocytes, macrophages, dendritic cells, monocytes, mast cells, lung epithelial cells, liver hepatocytes, and neurons throughout the CNS and enteric nervous system. On vascular endothelium, VPAC1 mediates vasodilation through nitric oxide (NO) generation. In immune cells, VPAC1 is the predominant receptor driving VIP's anti-inflammatory effects [6][10].

VPAC2 is the dominant VIP receptor in smooth muscle (vascular, airway, gastrointestinal), the suprachiasmatic nucleus (SCN), pancreatic beta cells, and is selectively upregulated on activated T cells and upon stimulation of macrophages through TLR2/TLR4. In blood vessels, VPAC2 induces NO-independent vasodilation of smooth muscle. In the SCN, VPAC2 is essential for circadian synchronization [6][11][12].

PAC1 has minimal affinity for VIP (Kd >500 nM versus approximately 0.5 nM for PACAP) and primarily mediates PACAP-specific signaling. PAC1 is expressed on macrophages and some neuronal populations [5][16].

Signaling Cascades

The canonical VIP signaling pathway begins with ligand binding to VPAC1 or VPAC2, which activates the stimulatory G protein Gs-alpha. This stimulates adenylyl cyclase, producing cAMP from ATP. Elevated cAMP activates two major effector systems [4][6]:

1. PKA (protein kinase A): Phosphorylates CREB (cAMP response element-binding protein), activating transcription of anti-inflammatory genes. PKA also inhibits NF-kappaB-dependent transcription of pro-inflammatory cytokines by blocking IkappaB kinase activity and suppressing Jak1/Jak2-STAT1 signaling downstream of IFN-gamma.

2. Epac (exchange protein directly activated by cAMP): Activates Rap1 GTPase, contributing to cytoskeletal rearrangements, cell adhesion, and exocytosis.

Secondary signaling pathways include activation of phospholipase C (PLC) through Gq coupling (particularly at VPAC2), mobilizing intracellular calcium and activating protein kinase C (PKC). VIP also modulates the MAPK cascades (ERK1/2, JNK, p38) in a cell-type-dependent manner [4][6].

Vasodilation and Smooth Muscle Relaxation

VIP is one of the most potent endogenous vasodilators. The mechanism is dual: VPAC1 on endothelial cells triggers NO synthesis via endothelial NO synthase (eNOS), while VPAC2 on smooth muscle cells directly relaxes vascular smooth muscle through cAMP-dependent reduction in intracellular calcium [6][13]. In the airways, VIP released from NANC neurons relaxes bronchial smooth muscle, functioning as the primary bronchodilatory neuropeptide opposing cholinergic bronchoconstriction. In the gastrointestinal tract, VIP mediates descending relaxation in the peristaltic reflex and sphincter relaxation [21].

5. Researched Applications

Pulmonary Arterial Hypertension

Evidence level: Moderate (clinical pilot data; orphan drug designation)

VIP receptors are abundantly expressed on pulmonary artery smooth muscle and endothelium, and VIP deficiency has been observed in the serum and lung tissue of patients with idiopathic pulmonary arterial hypertension (IPAH) [13]. In a pioneering clinical study, Petkov and colleagues (2003) treated eight patients with IPAH using inhaled VIP (200 micrograms daily in four divided inhalations) for three months. The results were striking: mean pulmonary artery pressure decreased by approximately 14 mmHg, pulmonary vascular resistance fell, cardiac output improved, and 6-minute walk distance increased -- all without systemic side effects attributable to VIP's vasodilatory properties [13].

The mechanism involves VIP-mediated cAMP elevation in pulmonary artery smooth muscle cells (causing relaxation and antiproliferative effects) and suppression of vascular remodeling. Aviptadil holds FDA orphan drug designation for pulmonary hypertension, and additional inhaled VIP studies have confirmed hemodynamic improvements in PAH patients [13][23].

ARDS and COVID-19 (Aviptadil/Zyesami)

Evidence level: Moderate (Phase IIb/III trial completed; FDA fast track designation)

VIP has a high concentration of receptors on alveolar type II (ATII) cells, which are responsible for surfactant production and alveolar repair. VIP binding to VPAC1 on ATII cells inhibits apoptosis, suppresses cytokine release, and preserves surfactant production -- properties that made it a strong candidate for ARDS treatment [14][23].

During the COVID-19 pandemic, aviptadil received FDA fast track designation for treatment of critical COVID-19 with respiratory failure. The Phase IIb/III COVID-AIV trial (NCT04311697) enrolled 196 patients with critical COVID-19 and respiratory failure. Intravenous aviptadil was administered at escalating doses (50, 100, and 150 pmol/kg/hr over 12 hours daily for three days). Results demonstrated [14]:

• No serious drug-related adverse events in the aviptadil arm
• A trend toward improved survival and respiratory recovery at day 60 (OR 1.6; 95% CI 0.86-3.11), though the primary endpoint did not reach statistical significance
• Subgroup analysis showed greater benefit in patients on high-flow nasal oxygen

Separately, inhaled aviptadil formulations (Zyesami) were evaluated in additional trials (NCT04360096, NCT05137795) for severe COVID-19 ARDS. VIP's mechanism in ARDS involves blocking the cytokine storm through inhibition of TNF-alpha, IL-6, and IL-12, reducing HMGB1 (a late inflammatory mediator), preserving ATII cell viability, and maintaining surfactant production [14][23].

Immune Modulation and Autoimmune Disease

Evidence level: Strong (extensive preclinical; pioneering immunology research)

The immunomodulatory properties of VIP have been characterized most thoroughly by the groups of Mario Delgado and Doina Ganea, whose work since the late 1990s has established VIP as a master regulator of immune homeostasis [7][8][9][10][16]. VIP's immunological effects operate at multiple levels:

Macrophage deactivation: VIP potently inhibits production of pro-inflammatory mediators from activated macrophages and microglia, including TNF-alpha, IL-6, IL-12, iNOS (nitric oxide synthase), COX-2, and HMGB1. Simultaneously, VIP upregulates the anti-inflammatory cytokine IL-10. These effects are mediated primarily through VPAC1 and the cAMP/PKA pathway, which suppresses NF-kappaB nuclear translocation and blocks IFN-gamma-induced Jak/STAT signaling [7][10].

Th1/Th2 balance: VIP inhibits the differentiation and expansion of pro-inflammatory Th1 cells while promoting Th2 immunity. The mechanism is multifold: VIP reduces IL-12 production by antigen-presenting cells (essential for Th1 polarization), blocks IL-12 signaling through JAK2/STAT4 in T cells, induces the Th2 transcription factors c-Maf and JunB, and promotes survival of Th2 cells while increasing Th1 susceptibility to apoptosis via FasL/granzyme B [7][16].

Regulatory T cell induction: VIP generates tolerogenic dendritic cells (tDCs) characterized by low expression of costimulatory molecules (CD40, CD80, CD86), reduced IL-12 production, and high IL-10 secretion. These VIP-induced tDCs drive the differentiation of CD4+Foxp3+ regulatory T cells (Tregs) that suppress proliferation of syngeneic and allogeneic T cells [8][9]. VIP also promotes Treg expansion through direct effects on naive T cells via VPAC2.

Chemokine modulation: VIP reduces production of pro-inflammatory chemokines (CXCL1, CXCL2, CCL2, CCL3, CCL4, CCL5, CXCL10) from macrophages and microglia, while promoting Th2-attracting chemokines such as CCL22. This shifts immune cell recruitment patterns away from inflammatory infiltration [10][16].

In animal models, VIP administration (typically 1-5 nmol i.p.) has demonstrated therapeutic efficacy in collagen-induced arthritis, experimental autoimmune encephalomyelitis (EAE/multiple sclerosis model), TNBS- and DSS-colitis, type 1 diabetes, autoimmune uveoretinitis, and Sjogren's syndrome [7][10][16]. VIP-pulsed tolerogenic dendritic cell therapy has been shown to halt disease progression in established arthritis models, representing a cellular therapy approach that circumvents VIP's short plasma half-life [8][9].

Neuroprotection

Evidence level: Moderate (strong preclinical data)

VIP exerts neuroprotective effects through both direct and indirect mechanisms. Directly, VIP stimulates the release of glial-derived neurotrophic factors, most notably activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP), which provide protection at femtomolar concentrations [17]. Indirectly, VIP suppresses neuroinflammation by deactivating microglia and reducing production of neurotoxic mediators (TNF-alpha, IFN-gamma, reactive oxygen species) [17][19].

Parkinson's disease: VIP and its superactive analogue stearyl-Nle17-VIP (SNV, approximately 100-fold more potent than VIP) protected dopaminergic neurons against MPTP-induced toxicity in both primary cultures and in vivo mouse models. The mechanism involves blocking microglial activation and raising cellular resistance to oxidative stress through ADNF/ADNP release [17]. VPAC2-selective agonists facilitate immune transformation from pro-inflammatory to neuroprotective phenotypes by inducing regulatory T cells that attenuate nigrostriatal neuroinflammation [20].

Alzheimer's disease: VIP markedly enhanced microglial phagocytosis of fibrillar amyloid-beta 42 through PKC-dependent signaling and reduced amyloid plaque deposition in APP/PS1 transgenic mice [18]. VIP also inhibits amyloid-beta-induced neurodegeneration by suppressing the release of inflammatory and neurotoxic factors from activated microglia [19].

Circadian Rhythm Regulation

Evidence level: Strong (established molecular mechanism)

VIP is the leading candidate molecule responsible for intercellular synchronization within the suprachiasmatic nucleus (SCN), the master circadian pacemaker [11][12]. Approximately 10-20% of SCN neurons express VIP, concentrated in the ventrolateral "core" region that receives direct retinal input through the retinohypothalamic tract. These retinorecipient VIP neurons relay photic timing information to the broader SCN network [11].

VIP signals through VPAC2 receptors on neighboring SCN neurons. Loss of VIP or VPAC2 abolishes circadian firing rhythms in approximately half of SCN neurons and disrupts synchrony among rhythmic neurons, leading to behavioral arrhythmicity and disrupted sleep-wake cycles in knockout mice [11]. The molecular mechanism involves VIP-VPAC2 activation of ERK1/2 signaling, which is tuned by the negative regulator DUSP4 (dual-specificity phosphatase 4) to enable circadian re-programming of clock gene expression [12].

VIP also plays a role in peripheral circadian coordination. VIP-deficient mice show attenuated rhythms of clock gene expression not only in the SCN but also in peripheral organs, suggesting VIP contributes to systemic circadian coherence [11][12].

Inflammatory Bowel Disease

Evidence level: Moderate (preclinical models; clinical rationale)

VIP is abundantly expressed in enteric neurons throughout the gastrointestinal tract, where it regulates motility, water and ion transport, mucus secretion, and mucosal immune homeostasis [21][22]. Loss of intestinal VIP levels has been implicated in the pathogenesis of both human IBD and rodent colitis models [22].

In TNBS-induced Crohn's disease models, VIP administration (1-5 nmol) reduced clinical and histopathologic severity of colitis and decreased Th1 cytokine levels [7][22]. However, systemic VIP delivery is limited by rapid degradation and dose-limiting hypotension. Nanomedicine approaches offer a solution: VIP encapsulated in sterically stabilized micelles (VIP-SSM) at 0.25 nmol reversed colitis-associated inflammation and diarrhea more effectively than free VIP, without causing systemic hypotension [25].

Erectile Dysfunction

Evidence level: Moderate (established physiological role; clinical combination therapy)

VIP is released from cavernous NANC nerve terminals along with nitric oxide and acetylcholine during erectile response. VIP activates adenylyl cyclase in corporal smooth muscle, raising cAMP and reducing intracellular calcium to facilitate smooth muscle relaxation and penile engorgement [4].

While intracavernosal VIP alone does not reliably induce full erection (unlike NO-based approaches), the combination product Invicorp (VIP 25 micrograms plus phentolamine 1-2 mg) has been used clinically for erectile dysfunction, particularly in patients who do not respond to phosphodiesterase-5 inhibitors. The combination approach leverages VIP's cAMP-dependent relaxation alongside phentolamine's alpha-adrenergic blockade [16].

6. VIPoma Syndrome

VIPomas are rare neuroendocrine tumors (annual incidence approximately 1 per 10 million) that pathologically hypersecrete VIP, producing the clinical syndrome first described by Verner and Morrison in 1958 [24]. The syndrome -- known as WDHA (watery diarrhea, hypokalemia, achlorhydria), Verner-Morrison syndrome, or pancreatic cholera -- results from VIP's physiological actions amplified to pathological extremes.

Clinical features include profuse secretory diarrhea (often >3 liters/day, watery, odorless, persisting with fasting), hypokalemia (from massive intestinal potassium loss, causing muscle weakness and cardiac arrhythmias), achlorhydria or hypochlorhydria (VIP inhibits gastric acid secretion), hyperglycemia (VIP stimulates hepatic glycogenolysis), hypercalcemia, and flushing episodes [24].

Pathology: Approximately 90% of VIPomas arise in the pancreas (predominantly body and tail), are typically solitary, and range from 1-7 cm in diameter. Approximately 60-80% are malignant at diagnosis, with hepatic metastases common. Extra-pancreatic VIPomas can originate from ganglioneuromas, ganglioneuroblastomas, or pheochromocytomas [24].

Diagnosis requires serum VIP levels >200 pg/mL (normal <190 pg/mL) in the context of secretory diarrhea. Imaging with CT, MRI, or somatostatin receptor scintigraphy (OctreoScan) localizes the tumor [24].

Treatment: Somatostatin analogues (octreotide, lanreotide) control diarrhea and reduce VIP secretion in most patients. Surgical resection is curative for localized tumors, with a 5-year survival rate of approximately 95% for benign resectable disease. Metastatic VIPomas carry a poorer prognosis but may respond to cytoreductive surgery, peptide receptor radionuclide therapy (PRRT), or chemotherapy [24].

7. Comparison with PACAP

Pituitary adenylate cyclase-activating polypeptide (PACAP) is VIP's closest structural relative, sharing approximately 68% amino acid sequence identity. Both peptides are members of the glucagon/secretin superfamily and signal through overlapping receptor systems. However, key pharmacological differences have important biological and therapeutic implications [4][5]:

| Feature | VIP | PACAP | |---|---|---| | Length | 28 amino acids | 38 or 27 amino acids (PACAP-38, PACAP-27) | | Receptor affinity | VPAC1 ~1 nM; VPAC2 ~1 nM; PAC1 >500 nM | VPAC1 ~1 nM; VPAC2 ~1 nM; PAC1 ~0.5 nM | | Selective receptor | None (shared VPAC1/VPAC2) | PAC1 (1000-fold selectivity over VIP) | | Dominant immune role | Anti-inflammatory, Th2/Treg induction | Overlapping; more neurotrophic emphasis | | Circadian role | Primary SCN synchronizer via VPAC2 | Photic entrainment signal to SCN | | Half-life | ~1-2 minutes | ~5-10 minutes | | Clinical development | Aviptadil (ARDS, PAH) | Limited clinical candidates |

The critical distinction is at the PAC1 receptor: PACAP binds with approximately 1000-fold greater affinity than VIP, enabling PACAP-specific signaling in neurons, adrenal chromaffin cells, and select immune populations where PAC1 predominates [5]. This receptor selectivity means that while VIP and PACAP share VPAC1/VPAC2-mediated effects (vasodilation, immune modulation), PACAP has additional PAC1-mediated functions in neuronal survival, synaptic plasticity, and stress responses that VIP cannot efficiently activate [4][19].

For drug development, the 56% sequence homology between PAC1 and VPAC1 and the cross-reactivity of native peptides have posed significant challenges in developing receptor-selective agonists and antagonists [5].

8. Safety Profile

VIP has a favorable safety profile when administered via appropriate routes, though its potent vasodilatory activity requires hemodynamic monitoring during intravenous delivery [13][14][23].

Intravenous aviptadil: The Phase IIb/III COVID-AIV trial (196 patients) reported no serious drug-related adverse events. The most commonly observed effects include dose-dependent transient hypotension and compensatory tachycardia, facial flushing, and diarrhea. The extremely short plasma half-life (1-2 minutes) limits systemic accumulation and provides a natural safety margin [14].

Inhaled VIP: Inhalation delivery offers a markedly improved safety profile. In the pulmonary hypertension study (200 micrograms daily for 3 months), virtually no patients experienced systemic side effects. The inhaled route delivers VIP directly to pulmonary vasculature and ATII cells while minimizing systemic exposure [13].

Nasal administration: VIP nasal spray formulations are generally well tolerated, with mild effects including nasal discomfort, transient headache, flushing, and occasional dizziness.

Key considerations:

• VIP's short half-life necessitates sustained infusion or alternative delivery strategies for systemic applications
• Sensitivity to peptidase degradation (NEP, DPP-IV) in plasma limits oral and injectable bioavailability
• Mitigation strategies under development include chemically stabilized VIP analogues, nanomedicine encapsulation (sterically stabilized micelles), peptidase-resistant modifications, and cellular therapy approaches (VIP-pulsed tolerogenic DCs) [16][25]

9. Dosing in Research

VIP is an endogenous neuropeptide with no standardized approved human dosing regimen. Dosing in clinical and preclinical research has varied by route and indication:

• Inhaled (pulmonary hypertension): 200 micrograms daily in four divided inhalations (50 micrograms each) [13]
• Intravenous (ARDS/COVID-19): Escalating doses of 50, 100, and 150 pmol/kg/hr over 12-hour infusions for three consecutive days [14]
• Intracavernosal (erectile dysfunction): 25 micrograms VIP combined with 1-2 mg phentolamine (Invicorp formulation)
• Preclinical immune modulation (mice): 1-5 nmol (approximately 3-17 micrograms) by intraperitoneal injection, typically repeated 5 times across a disease course [7][16]
• Nanomedicine (VIP-SSM): 0.25 nmol as sterically stabilized micelle formulation in murine colitis models [25]

10. Clinical Evidence Summary

11. Related Peptides

See also: Substance P, CGRP (Calcitonin Gene-Related Peptide), Neuropeptide Y, Oxytocin, Adrenomedullin

12. References

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