INTRODUCTION:
Of all the problems for which patients consult a neurologist headache are the most common and the most prevalent illnesses whose biology underlies these kinds of conditions are primary headaches, which includes migraine and cluster headache.1 Headache problems are frequently fatal, have a large influence on social activities and jobs, and may contribute to an extensive amount of drug usage. This is likely due to the short-term character of headaches and their low fatality rate. Our knowledge of the extent and distribution of the global health issue presented by the two basic primary headache types-tension-type headache and migraine-has been elucidated by recent research investigations.2 Clitoria ternatea also known as butterfly pea is an herbaceous perennial climber plant. Both in garden spaces and outside of them, this tropical flower is widespread. Clitoria ternatea belongs to the Fabaceae family, the class Magnoliopsida, the phylum Tracheophyte, and the kingdom Plantae. It is indigenous to Guinea, Ghana, Indonesia, Malaysia, and Zimbabwe. However, it was also brought to tropical regions of South Africa, America, and Australia. The bloom of C. ternatea has several physical and mental well-being advantages and is high in blue anthrocyanin.3 In C. ternatea, a variety of secondary metabolic products have been identified, such as lactones, flavanol glycosides, quercetin, kaempferol, and anthrocynin. Diuretic, antipyretic, insecticidal, smooth muscle relaxant, antimicrobial, local anesthetic, antidiabetic, anti-inflammatory, and analgesic qualities are only a few of the many medicinal properties in its extracts of plants.4 Nine chemicals have been identified so far from the extract, which mostly consisted of flavonoids. The aqueous extract reduced agents of inflammation and oxidative stress.5 This review emphasizes how Clitoria ternatea has analgesic and anti-inflammatory properties that help with headaches.
Headache:
Similar to drowsiness headache is a frequently appearing ailment in acute care hospitals and outpatient clinics. Over 200 different types of headaches have been identified to far, giving the incorrect belief that diagnosing and treating these diseases is extremely difficult.6
Headache is classified as:
Figure 1: Headache classification
When a primary headache occurs, it is a medical condition unto itself rather than a sign of something else. On the other hand, a secondary headache is a sign of a separate illness, such as a tumor or cerebral hemorrhage.7
Etiology of headache:
1. Primary headaches:
a. Tension type headache:
Tension-type headaches are very prevalent, they rank among the most expensive illnesses in contemporary society. The following mechanisms can result in tension-type headaches:
Peripheral mechanism:
Headaches may be preceded by myofascial stiffness. Tension-type headaches occur more frequently and are more intense when muscles are strained. Tension-type headaches are frequently caused by changes in the structure of the jaw, shoulder, and pericranial muscles.
Central mechanism:
Although disagreements over emotions and mental health issues are commonly linked to tension-type headaches, the exact connection between the two is unclear.8 The descending pain modulatory system's impaired regulatory and suppressive ability is another possible factor. These consist of components like diffuse noxious inhibitory controls (DNICs), which have the ability to block trigeminal and spatial neurons.9
b. Migraine:
A migraine episode is a very complicated brain case that can last anywhere from a few hours to many days. Typically, migraines are characterized by "pulsating," "throbbing," or "pounding" pain. It starts with a series of premonitory signs that may include the neurotransmitter dopamine and are linked to hypothalamic stimulation. Certain chemical signals of migraine have been identified, including pituitary adenylate cyclase-activating polypeptide, nitric oxide, prostanoids, serotonin receptors and calcitonin gene-related peptide.10
c. Cluster-type headache:
The neurovascular theory served as the foundation for the initial theories regarding cluster headache (CH), which were motivated by the actions of vasoactive compounds in the condition (narrowing halting episodes, dilation initiating them). Subsequent research has focused on the hypothalamus due to the recurrence of cluster headaches (CH), with better results. Studies using Positron Emission Tomography (PET) have demonstrated that the posterior hypothalamus is activated during cluster headache episodes, supporting the theory that the hypothalamus might be the source of cluster headaches. Studies using voxel-based morphometry showed that individuals with cluster headaches had a larger gray matter volume in the posterior hypothalamus than did controls. That theory is further supported by the effectiveness of hypothalamic deep-brain stimulation (DBS) and new data suggesting the role of the hypocretin receptor gene. Alterations in the hypothalamic-pituitary-adrenal axis's functioning may be connected to abnormal blood levels of cortisol testosterone, prolactin and thyroid stimulating hormone (TSH). The amounts of opiates, cytokines, neuropeptides, amines, nitric oxide, monoamine oxidase, prostaglandins, serotonin, and histamine can vary significantly from those of controls who are not impacted. The trigeminal-autonomic reflex in the brainstem circuitry, through the seventh cranial nerve, mediates the parasympathetic activation.11 Affected controls are thought to be involved in a different process that underlies CH inflammation caused by neurons. Electrical stimulation of the triglycerides in rats caused mast cell degranulation, production of Calcitonin Gene-Related Peptide, plasma protein extravasation, and vacuolation in post-capillary venule endothelial cells every one of which is indicative of neurogenic inflammation.12
2. Secondary headaches:
Among the most common symptoms frequently linked to brain tumors is headache. Secondary headaches are caused by intracranial neoplasias that have either drastically improved after the neoplasia has been successfully treated or have significantly deteriorated in tandem with the tumor's deterioration.13 A common sign of paranasal sinus lesions is headache. Usually the main showing sign is an irregular headache, even if some inflammatory symptoms may indicate paranasal sinus diseases.14 Some hypertensive individuals experience headaches as a result of periodic or circadian pressure stimulation of pressure-responsive eye nerve fibers, which may be caused by the occurrence of relatively rapid eye congestion through High Blood pressure-induced choroidal overload.15
Pathophysiological understanding as well as clinical data provide strong clinical proof that drugs like cocaine, NO donors, and phosphodiesterase inhibitors can produce headaches in patients who are healthy.16
Pathophysiology of headache:
The absence of pain receptors in the brain makes it insensitive to pain. Certain parts of the head and neck are capable of feeling pain because they have pain receptors. These consist of the middle meningeal artery, big veins, and extracranial arteries. The falx cerebri and meninges, the venous sinuses, the sinus nerves, the cranial, the brainstem, the head and neck muscles, the eyes, ears, teeth, and the oral mucosa. Headache and pain generation are caused by the pial arteries, not the pial veins. The cause and treatment of primary headaches are highlighted in this section.17
1. Migraine type headache:
Researchers' studies have been significantly impacted by the pathophysiology of migraines, which is either neurological or vascular. On either hand, migraine headaches are vascular, and on the other side, the trigeminal vascular system may be activated to cause migraine discomfort. Three factors contribute to migraine pain:
a. Sudden-onset of neurogenic inflammation in the perivascular region;
b. Vasodilation, mostly of the intracranial blood vessels; and
c. Stimulation of the central trigeminal network, which includes the trigeminal nucleus caudalis and also it’s centrally connections. The pathophysiology of migraine is attempted to be explained by two distinct ideas.
Vascular theory:
According to this view, migraine aura is caused by the brain's arteries constricting. In the mid-20th century, specifically during the 1940s and 1950s, researchers introduced the vascular theory as a potential explanation for the underlying mechanisms of migraine headaches. This theory focused on the role of blood vessels and their changes in the development of migraines. The migraine aura is caused by ischemia brought on by cerebral vasoconstriction, while the headache is an outcome of rebound vasodilation and perivascular nociceptive neuron stimulation.
Neurovascular hypothesis:
According to this idea, a migraine is caused by a complicated chain of vascular and neurological events. This theory states that the primary cause of migraine is neurogenesis, with secondary alterations in cerebral perfusion. The cerebral cortex, particularly the occipital cortex, is in a condition of neuronal hyperexcitability in a migraineur who is not experiencing any headaches at baseline. Studies using functional magnetic resonance imaging (MRI) and transcranial magnetic stimulation have shown this result. According to the neurovascular theory, the stimulation and inhibition of neurons that propagate throughout the brain's gray matter cause migraine aura. Cortical spreading depression is the term used to describe this spreading phenomenon.18
Figure 2: Pathophysiology of migraine
2. Tension type headache:
Alterations in the down regulation of second-order trigeminal brainstem nociceptors may interact with corresponding peripheral alterations, including strain in the pericranial muscles and myofascial pain sensitivity, to cause tension-type headaches (TTH). Individuals in generally excellent health may experience an acute episode of episodic tension-type headache (ETTH), which can be triggered by nonphysiological positions of work or bodily strain, typically in conjunction with mental strain. In these situations, a central transient shift in pain management brought on by stress may favor enhanced nociception from strained muscles as the main source of the headache. Emotional processes decrease the activity in the endogenous antinociceptive system while simultaneously increasing muscle tension via the limbic system. The importance of central alterations increases with the frequency of headache episodes. Chronic Tension-Type Headache (CTTH) is a persistent disorder characterized by progressive worsening, linked to sustained sensitization of pain-processing neurons and diminished functioning of the body’s innate pain-suppression mechanisms; these central alterations likely prevail in recurrent CTTH. However, the corresponding importance of central and peripheral variables may change gradually in the same person as well as between people. The psychological and central changes that cause chronic tension-type headaches (CTTH) are probably influenced by genetic factors.19
Figure 3: The pathophysiology of CTTH
3. Cluster type headache:
The hypothalamus, a part of the brain that regulates physiological cycles throughout the day, is thought to be the source of cluster headaches. Cluster headaches were first associated with aberrant pituitary hormone levels in the 1970s and 1980s. Later PET (positron emission tomography) scans verified that the posterior hypothalamus was activated during episodes. Originally believed to be specific to cluster headaches, this is also observed in migraines. Although the precise source of its activation is uncertain, the trigeminal nerve transmits pain that occurs during these headaches. Some peptides are released upon activation, resulting in edema, vasodilation, and inflammation. Attacks result in higher concentrations of peptides including Vasoactive Intestinal Peptide (VIP) and Calcitonin Gene-Related Peptide (CGRP).
The sphenopalatine ganglion is activated by parasympathetic nerve fibers, resulting in symptoms including flushing, rhinorrhea, lacrimation, and conjunctival injection. Trigeminal pain signals are responsible for reflex activation of these reactions. Furthermore, elevated face temperature and dilated cerebral arteries are noted. Additionally, some individuals have Horner-like symptoms such as ptosis (drooping eyelid) and miosis (constricted pupils), which may be brought on by sympathetic nerve disruption on the side that is affected.20
Plant Description:
Figure 4: Clitoria ternatea21
These are pea-shaped flowers with bilateral symmetry and a tubular calyx made up of fused sepals arranged in set of five and produces flowers that extend to approximately two-thirds of their total length. Five free petals make up the ostentatious corollae, which also has two folded wings that are frequently half along the length of the uppermost petel, two pale keels that help shield the floral organs, and a huge, spherical banner. The petals typically display a deep blue color, but they may also appear milky or a variety of blue and white hues. Ten filaments make up the stamens in two bundles, nine of which are united and one of which is separate. Each filament has a pollen-producing, pale anther with a four-part division attached to it. A unicarpellate ovary with 10 ovules is produced by C. ternatea. This is overcome by a thick, lengthy style with a curved tip. Around the world, the Clitoria plant is found in equatorial and warm-temperate climates. Since Linnaeus derived the specific description from specimens found on the Indonesian archipelago's island of Ternate, the etymology of the particular name is assumed to originate there. The species' natural range is unclear because ternate is found in eastern Indonesia and the Molucca Sea rather than the Indian Ocean. All other species in the subgenus Clitoria are found only in Madagascar, India, Africa, and various islands in the Western Indian Ocean region.22
Figure 5: Structures of identified compounds
Chemical constituents:
From Clitoria ternatea, a variety of secondary metabolites have been identified, like flavanoid glycosides, triterpenoids, quercetin, lactones, anthrocyanins, and kaempferol.23,24,21
Because of its well-known anti-inflammatory and antioxidant qualities, kaempferol and quercetin are used to alleviate headaches. Their mode of action is as follows:
1. Anti-inflammatory activity: By the inhibition of enzymes like lipoxygenase (LOX) and cyclooxygenase (COX) quercetin and kaempferol prevent the synthesis of pro-inflammatory chemicals like cytokines, prostaglandins, as well as leukotrienes.25,26
2. Antioxidant activity: Quercetin and kaempferol have strong antioxidant properties that assist the body in fighting off free radicals and oxidative stress.27
3. Blood vessel dilation: By regulating the synthesis of nitric oxide, a chemical that affects blood vessel dilatation, quercetin and kaempferol have been demonstrated to enhance vascular health.28,29
4. Mast cell stabilization: Mast cells, associated with the secretion of histamine along with other inflammatory mediators, can be stabilized by quercetin.30
Scientific Evidence on Clitoria Ternatea for Headaches:
There is currently little scientific research examining Clitoria ternatea's effects on headaches, despite the plant's widespread use in conventional healthcare for its therapeutic advantages. But in one study, Clitoria ternatea tea's DPPH radical inhibition assay was evaluated against the plant's extract and a sample of standard with water. The results showed that the extract had a significantly larger (p < 0.05) antioxidant capacity, which may help lessen the pain associated with different kinds of headaches.31 In another investigation, two animal models—carrageenan-induced paw edema and histamine-induced paw edema—were used to measure the anti-inflammatory effects of the Clitoria ternatea extract. To test a drug's anti-inflammatory properties during the early stage of inflammation, a carrageenan-induced paw edema model was employed. Carrageenan injected subplantarly into the rat paw causes plasma increased vascular permeability and inflammatiory reactions which are symptoms of increased exudation of water in tissue and plasma proteins, neutrophil extravasation, and arachidonic acid metabolism by the enzyme pathways LOX and COX. Carrageenan-induced edema occurs in two stages. Serotonin and histamine are released during the first phase (one hour), while prostaglandins influence the second phase (more than an hour). For five hours, the mean edema volume and percentage inhibition were computed. Clitoria ternatea extract dosages demonstrated a strong anti-edematous effect during the second stage of inflammation, suggesting that prostaglandin release was inhibited. The third and fourth hours were when the highest percentage inhibition was seen. Clitoria ternatea's extract potency was determined to be comparable with that of marketed NSAID. In the histamine-induced rat paw edema model, the two extract dosages significantly inhibited.
The efficiency of the plant extract in suppressing edema may be attributed to its capacity to prevent the production, release, or activity of histamine contributing to inflammation. It was shown that the extract was able to reduce the histamine induced edema. Significant anti-inflammatory benefits were shown, which may help lessen the discomfort brought on by different kinds of headaches.32
Clitoria ternatea has traditionally been used to treat a number of ailments, including headaches. Clitoria ternatea blossoms are frequently used to make tea or eaten in different ways to relieve tension, headaches, and lightheadedness. Clitoria ternatea flower paste is used to treat headaches, as per the Irulas of the Kodiakkarai.33
Benefits:
1. Clitoria ternatea demonstrated a wide range of pharmacological properties, including antipyretic, gastro-intestinal, antiparasitic, insecticidal, antibacterial, anticancer, analgesic, and analgesic.
2. A remedy for snake bites was made using juice and flowers.34
3. It may be possible to exploit and develop the anthocyanin-rich portion of C. ternatea as a nutraceutical agent or functional food ingredient.35
Potential side effects:
As of right now, drinking blue tea has no known negative consequences. However, anecdotal research suggests that excessive use may result in diarrhea, stomach pain, and nausea.34
Comparative Advantages of Herbal formulations over Conventional Synthetic Headache Medication:
Despite the fact that many synthetic medications are beneficial to mankind and follow best practices, several medications are nonetheless known to have serious adverse effects. The majority of over-the-counter medications, such as aspirin, ibuprofen, diclofenac, clopidogrel, enoxaparin, warfarin, and naproxen, have mild to severe adverse effects (such as hemorrhage, heavy bleeding, and breathing difficulties). Homemade cures, medicinal plants, and herbs like Clitoria ternatea have a lower cost than. The bulk of individuals in rural and underdeveloped areas have naive trust in synthetic drugs. They are correct since they have no deadly adverse effects and can be utilized for managing any illness. Even though herbal remedies can occasionally be less effective than synthetic pharmaceuticals, they are nonetheless thought to be less harmful or to have fewer adverse effects.36
CONCLUSION:
Clitoria ternatea, with its rich profile of bioactive compounds such as flavonoids, anthocyanins, and triterpenoids, offers promising therapeutic benefits for managing headaches. The plant’s anti-inflammatory, antioxidant, and analgesic properties make it a viable natural remedy, particularly for primary headaches like migraines and tension-type headaches. Scientific studies have begun to substantiate traditional uses of C. ternatea by showing its effectiveness in reducing inflammation and oxidative stress, two key factors in headache pathophysiology. Although herbal remedies, including C. ternatea, may be less potent than synthetic drugs, they present fewer side effects and remain accessible and cost-effective for broader populations. Future research should focus on standardizing dosages, understanding the specific mechanisms of action in headache relief, and conducting clinical trials to confirm its efficacy and safety. Integrating Clitoria ternatea into modern headache treatments could provide a complementary approach to existing therapies, combining the strengths of both traditional and pharmaceutical practices for better patient outcomes.
REFERENCES:
1. Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick D. Towards a definition of intractable headache for use in clinical practice and trials. Cephalalgia. 2006 Sep; 26(9): 1168-70.
2. Rasmussen BK. Epidemiology of headache. Cephalalgia. 2001 Sep; 21(7): 774-7.
3. Multisona RR, Shirodkar S, Arnold M, Gramza-Michalowska A. Clitoria ternatea flower and its bioactive compounds: Potential use as microencapsulated ingredient for functional foods. Applied Sciences. 2023 Feb 7; 13(4): 2134.
4. Mukherjee PK, Kumar V, Kumar NS, Heinrich M. The Ayurvedic medicine Clitoria ternatea—From traditional use to scientific assessment. Journal of Ethnopharmacology. 2008 Dec 8; 120(3): 291-301.
5. Wang Y, Liu T, Xie Y, Li N, Liu Y, Wen J, Zhang M, Feng W, Huang J, Guo Y, Junior TK. Clitoria ternatea blue petal extract protects against obesity, oxidative stress, and inflammation induced by a high-fat, high-fructose diet in C57BL/6 mice. Food Research International. 2022 Dec 1; 162: 112008.
6. Ahmed F. Headache disorders: differentiating and managing the common subtypes. British journal of pain. 2012 Aug; 6(3): 124-32.
7. May A. Hints on diagnosing and treating headache. Deutsches Ärzteblatt International. 2018 Apr; 115(17): 299.
8. Jensen R. Peripheral and central mechanisms in tension-type headache: an update. Cephalalgia. 2003 May; 23(1_suppl): 49-52.
9. Hernandez J, Molina E, Rodriguez A, Woodford S, Nguyen A, Parker G, Lucke-Wold B. Headache disorders: differentiating primary and secondary etiologies. Journal of Integrative Neuroscience. 2024 Feb 20; 23(2): 43.
10. Charles A. The evolution of a migraine attack–a review of recent evidence. Headache: The Journal of Head and Face Pain. 2013 Feb; 53(2): 413-9.
11. Leroux E, Ducros A. Cluster headache. Orphanet Journal of Rare Diseases. 2008 Dec; 3 :1-1.
12. Gibson KF, Santos AD, Lund N, Jensen R, Stylianou IM. Genetics of cluster headache. Cephalalgia. 2019 Sep; 39(10): 1298-312.
13. Palmieri A, Valentinis L, Zanchin G. Update on headache and brain tumors. Cephalalgia. 2021 Apr; 41(4): 431-7.
14. Lin SH, Ho CY. Paranasal sinus pathologies in patients presenting with headache as the primary symptom. Cephalalgia. 2006 Apr; 26(4): 423-7.
15. Gupta VK. Systemic hypertension, headache, and ocular hemodynamics: a new hypothesis. Medscape General Medicine. 2006; 8(3): 63.
16. Toom K, Braschinsky M, Obermann M, Katsarava Z. Secondary headache attributed to exposure to or overuse of a substance. Cephalalgia. 2021 Apr; 41(4): 443-52.
17. Jensen R. Pathophysiological mechanisms of tension-type headache: a review of epidemiological and experimental studies. Cephalalgia. 1999 Jul; 19(6): 602-21.
18. Wagh, Mahesh and Mane, Dhananjay. (2022). Migraine-the periodic attacks and impact of medications.
19. Fumal A, Schoenen J. Tension-type headache: current research and clinical management. The Lancet Neurology. 2008 Jan 1; 7(1): 70-83.
20. Alstadhaug KB, Ofte HK. Klasehodepine. Tidsskrift for Den norske legeforening. 2015 Aug 25.
21. Lijon MB, Meghla NS, Jahedi E, Rahman MA, Hossain I. Phytochemistry and pharmacological activities of Clitoria ternatea. International Journal of Natural and Social Sciences. 2017 Jan; 4(1): 1-0.
22. Oguis GK, Gilding EK, Jackson MA, Craik DJ. Butterfly pea (Clitoria ternatea), a cyclotide-bearing plant with applications in agriculture and medicine. Frontiers in Plant Science. 2019 May 28; 10: 645.
23. Ali Z, Ganie SH, Narula A, Sharma MP, Srivastava PS. Intra-specific genetic diversity and chemical profiling of different accessions of Clitoria ternatea L. Industrial Crops and Products. 2013 May 1; 43: 768-73.
24. Chayaratanasin P, Caobi A, Suparpprom C, Saenset S, Pasukamonset P, Suanpairintr N, Barbieri MA, Adisakwattana S. Clitoria ternatea flower petal extract inhibits adipogenesis and lipid accumulation in 3T3-L1 preadipocytes by downregulating adipogenic gene expression. Molecules. 2019 May 17; 24(10): 1894.
25. M Calderon-Montano J, Burgos-Morón E, Pérez-Guerrero C, López-Lázaro M. A review on the dietary flavonoid kaempferol. Mini Reviews in Medicinal Chemistry. 2011 Apr 1; 11(4): 298-344.
26. Comalada M, Ballester I, Bailón E, Sierra S, Xaus J, Gálvez J, de Medina FS, Zarzuelo A. Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure–activity relationship. Biochemical Pharmacology. 2006 Oct 16; 72(8): 1010-21.
27. Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. European Journal of Pharmacology. 2008 May 13; 585(2-3): 325-37.
28. Farhan M, Zafar A, Chibber S, Khan HY, Arif H, Hadi SM. Mobilization of copper ions in human peripheral lymphocytes by catechins leading to oxidative DNA breakage: A structure activity study. Archives of Biochemistry and Biophysics. 2015 Aug 15; 580: 31-40.
29. Loke WM, Hodgson JM, Proudfoot JM, McKinley AJ, Puddey IB, Croft KD. Pure dietary flavonoids quercetin and (−)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men. The American Journal of Clinical Nutrition. 2008 Oct 1; 88(4): 1018-25.
30. Wyss D, Bonneau O, Trifilieff A. Mast cell involvement in the adenosine mediated airway hyper-reactivity in a murine model of ovalbumin-induced lung inflammation. British Journal of Pharmacology. 2005 Aug 8; 145(7): 845.
31. Lakshan SA, Jayanath NY, Abeysekera WP, Abeysekera WK. A commercial potential blue pea (Clitoria ternatea L.) flower extract incorporated beverage having functional properties. Evidence‐Based Complementary and Alternative Medicine. 2019; 2019(1): 2916914.
32. Swathi KP, Jayaram S, Sugumar D, Rymbai E. Evaluation of anti-inflammatory and anti-arthritic property of ethanolic extract of Clitoria ternatea. Chinese Herbal Medicines. 2021 Apr 1; 13(2): 243-9.
33. Alok S, Gupta N, Malik AK. An update on ayurvedic herb vishnukanta (Clitoria ternatea Linn.): A.
34. Al-Snafi AE. Pharmacological importance of Clitoria ternatea–A review. IOSR Journal of Pharmacy. 2016 Mar; 6(3): 68-83.
35. Jeyaraj EJ, Lim YY, Choo WS. Antioxidant, cytotoxic, and antibacterial activities of Clitoria ternatea flower extracts and anthocyanin-rich fraction. Scientific Reports. 2022 Sep 1; 12(1): 14890.
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Received on 16.04.2025 Revised on 15.05.2025 Accepted on 04.06.2025 Published on 22.07.2025 Available online from July 26, 2025 Res.J. Pharmacology and Pharmacodynamics.2025;17(3):220-226. DOI: 10.52711/2321-5836.2025.00036 ©A and V Publications All right reserved
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